WO2015058589A1 - 吡啶酮类衍生物、其制备方法及其在医药上的应用 - Google Patents

吡啶酮类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2015058589A1
WO2015058589A1 PCT/CN2014/085976 CN2014085976W WO2015058589A1 WO 2015058589 A1 WO2015058589 A1 WO 2015058589A1 CN 2014085976 W CN2014085976 W CN 2014085976W WO 2015058589 A1 WO2015058589 A1 WO 2015058589A1
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group
fluoro
methyl
cancer
alkyl
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PCT/CN2014/085976
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English (en)
French (fr)
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屠汪洋
张海棠
徐国际
池江涛
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上海恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CN201480003661.8A priority Critical patent/CN104936945B/zh
Priority to EP14854930.6A priority patent/EP3061747B1/en
Priority to RU2016118753A priority patent/RU2667892C2/ru
Priority to US15/030,125 priority patent/US9914703B2/en
Application filed by 上海恒瑞医药有限公司, 江苏恒瑞医药股份有限公司 filed Critical 上海恒瑞医药有限公司
Priority to AU2014339527A priority patent/AU2014339527B2/en
Priority to BR112016007396-7A priority patent/BR112016007396B1/pt
Priority to JP2016518444A priority patent/JP6403172B2/ja
Priority to PL14854930T priority patent/PL3061747T3/pl
Priority to KR1020167012819A priority patent/KR102222569B1/ko
Priority to CA2927635A priority patent/CA2927635C/en
Priority to MX2016004742A priority patent/MX2016004742A/es
Priority to ES14854930T priority patent/ES2868450T3/es
Publication of WO2015058589A1 publication Critical patent/WO2015058589A1/zh
Priority to HK16101027.7A priority patent/HK1212980A1/zh
Priority to US15/719,138 priority patent/US10064848B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel pyridone derivative, a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use as a MEK inhibitor, particularly as a cancer therapeutic agent.
  • Silk/threonine mitogen-activated protein kinases are cells associated with tyrosine kinase receptors (such as EGF receptors) and/or G-protein heterotrimers Factor receptor activation interacts with a variety of intracellular signals evoked by different second messengers, phosphorylating and modulating the activity of various enzymes and transcription factors (eg NF- ⁇ B, Rsk 90, phospholipase A2, c- Myc, CREB, Ets-1, AP-1 and c-jun, etc.).
  • tyrosine kinase receptors such as EGF receptors
  • G-protein heterotrimers Factor receptor activation interacts with a variety of intracellular signals evoked by different second messengers, phosphorylating and modulating the activity of various enzymes and transcription factors (eg NF- ⁇ B, Rsk 90, phospholipase A2, c- Myc, CREB, Ets-1, AP-1 and c-jun, etc.).
  • Ras/Raf/MEK/Erk kinase pathway is one of the most clear and important pathways in the MAPK pathway involved in normal and abnormal cell growth. More than a decade ago, scientists discovered that the protein kinase family Erks proliferated. Subsequent studies quickly identified the upstream kinase MEK family of Erk, which in turn found that Raf activates MEKs, upstream of which is a G protein, and activated GTP binds to Ras. Indirectly activate Raf. About 30% of patients with malignant tumors have Ras gene mutations, while in pancreatic cancer, the Ras gene mutation rate is up to 90%.
  • B-Raf has a mutation rate of 50%-70% in melanoma, 35% in ovarian cancer, 30% in thyroid cancer, and 10% in colon cancer.
  • MEKs can also be activated by the Raf-independent kinase MEK kinase (also known as MEKK).
  • MEKs also known as MAP kinases (MAPKK or Erk kinase)
  • MAPKK MAP kinases
  • Erk 1 and Erk 2 are bispecific kinases that phosphorylate the silk/threonine residues and tyrosine of MAPK (p44 MAPK (Erk 1) and p42 MAPK (Erk 2)) Residues (Erk1 phosphorylation sites are T202 and Y204, Erk2 phosphorylation sites are T183 and Y185), and the MEK family contains five genes: MEK1, MEK2, MEK3, MEK4 and MEK5.
  • the N-terminus of MEKs is a negative regulatory region, and the C-terminal catalytic domain has the function of binding to Erks and activating Erks. It has been found that knocking out the regulatory region of MEK1 leads to inhibition of the intrinsic activity of MEK1 and Erk.
  • MEK1 has a molecular weight of about 44 kDa and contains a total of 393 amino acids. It is mainly expressed in adult tissues, especially brain tissues. A small amount of MEK1 expression can also be detected during embryonic development. MEK1 triggers its activity by phosphorylation of S218 and S222 sites. It was found that in NIH3T3 cells, the two residues were replaced with aspartic acid or glutamic acid, and their activity increased and colony formation increased. The intrinsic activity of MEK1 in primary cell culture promotes cell senescence and expression of p53 and p16 INK4a , whereas in immortalized cells and cells deficient in p53 or p16 INK4a , MEK1 acts in the opposite direction.
  • MEK2 has a molecular weight of approximately 45 kDa and a sequence similarity to MEK1 of 79%, and its activity is triggered by phosphorylation of the S222 and S226 sites.
  • MEK1 and MEK2 have different phosphorylation catalytic activities for different MAPK subtypes, Erk1 and Erk2.
  • MEK3, MEK4 and MEK5 do not play their role by acting on Erks.
  • sorafenib (Bay 43-9006) was launched in 2006 and is a non-specific silk/threonine and tyrosine kinase inhibitor. Its target includes Raf, MEK, VEGFR2/3, Flt-3, PDGFR, c. -Kit and so on.
  • B-Raf-specific inhibitors such as dabrafenib (GSK2118436) and vemurafenib (PLX4032) showed good clinical outcomes, but the duration was not long. At the same time, clinical studies found that patients who received PLX4032 were most likely to relapse with symptoms.
  • the present invention provides a novel structure of MEK inhibitor, and has found that the compound CYP450 having such a structure has a small inhibitory effect, has good activity, and exhibits an excellent anti-tumor cell proliferation effect.
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer and a mixture thereof, And pharmaceutically acceptable salts thereof:
  • R 1 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl or heteroaryl is independently independently optionally further selected from one or more Halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 , -C(O)NHR 7 , -NHC(O)R 7 , -NHC( Substituting O) OR 7 , -NHS(O) m R 7 , -NR 8 R 9 , -OC(O)NR 8 R 9 or -C(O)NR 8 R 9 ;
  • R 2 or R 3 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkenyl, alkynyl, heterocyclyl, Aryl, heteroaryl, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 ,- NHC (O) R 7, -NHC (O) oR 7, -NHS (O) m R 7, -NR 8 R 9, -OC (O) NR 8 R 9 or -C (O) NR 8 R 9 is Substituted by a substituent;
  • R 4 is selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, nitro, alkyl, haloalkyl, Hydroxyalkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C( O) OR 7 , -C(O)R 7 , -NHC(O)R 7 , -NHC(O)OR 7 , -NHS(O) m R 7 , -NR 8 R 9 , -OC(O)NR Substituted by a substituent of 8 R 9 or -C(O)NR 8 R 9 ;
  • R 5 is selected from a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group, wherein each of the alkyl, alkenyl or alkynyl groups is independently independently further optionally one or more selected from the group consisting of halogen, hydroxy, alkoxy, cyanide Substituted by a substituent of a haloalkyl group;
  • R 6 is selected from a hydrogen atom, a halogen or an alkyl group, wherein the alkyl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclic, Substituted by a substituent of an aryl or heteroaryl group;
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters;
  • R 8 or R 9 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group
  • the groups are each independently optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters.
  • R 8 or R 9 together with a nitrogen atom to which they are attached form a heterocyclic group, wherein said heterocyclic group contains one or more N, O or S(O) m heteroatoms, and said heterocyclic group Optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters;
  • n 0, 1 or 2;
  • n 0, 1, or 2.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof forms and mixtures thereof, and pharmaceutically acceptable salts thereof, in which R 1 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl group is optionally further substituted by one or more halo, cyano, nitro , alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 , -C(O)NHR 7 , -NHC(O)R 7 , -NHC(O)OR 7 , -NHSOR 7 , -NHS Substi
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof wherein R 2 is selected from a hydrogen atom, R 3 is selected from a hydrogen atom or an alkyl group, wherein said alkyl group is further further selected from one or more selected from the group consisting of halogens, Cyano, nitro, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 , -NHC(O)R 7 , -NHC(O)OR 7 , -NHS(O) m R 7 , -NR 8 R 9 ,- Substituents
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof a form and a mixture thereof, and a pharmaceutically acceptable salt thereof which is a compound represented by the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, or a non- Enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof:
  • R a or R b is selected from a hydrogen atom, a halogen, an alkyl group or a halogenated alkyl group;
  • R 1 is selected from phenyl or pyridyl, wherein said phenyl or pyridyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, haloalkyl, -OR 7 , -C(O)NHR 7 ,- Substituted by a substituent of NHC(O)R 7 , -NHC(O)OR 7 , or -NHS(O) m R 7 ;
  • R 6 is selected from a hydrogen atom, a halogen or an alkyl group, wherein the alkyl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclic, Substituted by an aryl or heteroaryl substituent;
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Further substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention also provides a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer and a mixture thereof, And a pharmaceutically acceptable salt thereof, which can be used as a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof.
  • R 1 , R 4 to R 6 are as defined in the general formula (I);
  • PG is selected from an alkyl or amino protecting group, wherein said amino protecting group is preferably a benzyl group, said alkyl or benzyl group being further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl Substituted with a cycloalkyl, heterocyclyl, heteroaryl or a substituent of -OR 7 ;
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Further substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters.
  • Typical compounds of the general formula (IA) of the present invention include, but are not limited to:
  • the present invention also provides a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer and a mixture thereof. And methods of pharmaceutically acceptable salts thereof, the method comprising:
  • R 1 , R 4 to R 6 are as defined in the formula (I);
  • -OG is a leaving group, preferably a sulfonyloxy group
  • PG is selected from an alkyl or amino protecting group, wherein said amino protecting group is preferably a benzyl group, said alkyl or benzyl group being further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl Substituted with a cycloalkyl, heterocyclyl, aryl, heteroaryl or a substituent of -OR 7 ;
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters;
  • the reagent for providing basic conditions includes an organic base and an inorganic base, and the organic base includes, but not limited to, triethylamine, pyridine, 2,6-lutidine, sodium methoxide, hexamethyl.
  • Lithium silicon hydride, sodium hexamethyldisilazide, n-butyl lithium, potassium t-butoxide or tetrabutylammonium bromide said inorganic bases including but not limited to sodium hydride, sodium carbonate, Sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide; preferably the reagent of basic conditions is an inorganic base, more preferably sodium hydride or cesium carbonate.
  • the present invention also provides a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer and a mixture thereof. And methods of pharmaceutically acceptable salts thereof, the method comprising:
  • the compound of the formula (IA) is ring-opened under basic conditions, optionally further deprotecting the amino protecting group PG to give a compound of the formula (I);
  • R 1 to R 6 are as defined in the general formula (I);
  • PG is selected from an alkyl or amino protecting group, wherein said amino protecting group is preferably a benzyl group, said alkyl or benzyl group being further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl Substituted with a cycloalkyl, heterocyclyl, aryl, heteroaryl or a substituent of -OR 7 ;
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters;
  • the reagent for providing basic conditions includes an organic base and an inorganic base, and the organic base includes, but not limited to, triethylamine, pyridine, 2,6-lutidine, sodium methoxide, hexamethyl.
  • Lithium silicon hydride, sodium hexamethyldisilazide, n-butyl lithium, potassium t-butoxide or tetrabutylammonium bromide said inorganic bases including but not limited to sodium hydride, sodium carbonate, Sodium bicarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide; in the method of the present invention, the reagent for ring-opening reaction is preferably an inorganic base, more preferably lithium hydroxide, Sodium hydroxide or sodium methoxide.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to the invention or a tautomer, a mesogen, a racemate, an enantiomer thereof , diastereomers and In the form of a mixture, and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting MEK.
  • the present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for treating a inflammatory disorder, an autoimmune disease, a cardiovascular disorder, a proliferative disorder or a symptomatic condition, wherein said proliferative disorder can For cancer (as defined below).
  • the present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating cancer, wherein the cancer is selected from the group consisting of melanoma, brain tumor (malignant astroglia and oligodendroglioma) Ingredients such as glioma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous carcinoma) Etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, test
  • the present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment of cancer, wherein the cancer is preferably colorectal cancer or lung cancer.
  • the invention also relates to a method of inhibiting MEK activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen, a racemate, a pair thereof Forms, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the invention relates to a method of treating an inflammatory condition, an autoimmune disease, a cardiovascular condition, a proliferative disease or a nociceptive condition comprising administering to a patient in need thereof a therapeutically effective amount of the formula (I) a compound or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, and mixtures thereof, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same
  • the proliferative disorder can be cancer (as defined below).
  • the invention further relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof Isomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, wherein the cancer is selected from the group consisting of melanoma, brain tumors (malignant astrocytes) And oligodendroglioma components such as glioma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, Primary or metastatic squamous cell carcinoma, etc., kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma
  • the present invention also relates to a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof as a drug which inhibits MEK activity. And mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the present invention also relates to a compound of the formula (I) or a tautomer thereof, mesogenic form thereof as a medicament for treating a inflammatory disorder, an autoimmune disease, a cardiovascular disorder, a proliferative disorder or a nociceptive disorder. , a racemate, an enantiomer, a diastereomer, and mixtures thereof, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the proliferative disorder may be cancer ( As defined below).
  • the present invention further relates to a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a drug for treating cancer a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of a melanoma, a brain tumor (a nerve having a malignant astroglia and a oligodendroglioma component) Glioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), Kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosar
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan An oleate, and a condensation product of the partial ester and ethylene oxide, such as polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; additionally, the preferred mode of treatment, such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt It can be verified according to traditional treatment options.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, an alkyl group having 1 to 6 carbon atoms is more preferred, and an alkyl group having 1 to 4 carbon atoms is most preferred, preferably a methyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, -OR 7 , -C(O)OR 7 , -OC ( O) R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 , -C(O)NHR 7 , -NHC(O)R 7 ,
  • Alkenyl means an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like. A C 2-10 alkenyl group is preferred, a C 2-6 alkenyl group is more preferred, and a C 2-4 alkenyl group is most preferred.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 n C(O)OR 7 , -C(O)R 7 , -C(O)NHR 7 , -NHC(O)R 7 , -NHC(
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • a C 2-10 alkynyl group is preferred, a C 2-6 alkynyl group is more preferred, and a C 2-4 alkynyl group is most preferred.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero A cycloalkylthio group, an oxo group, an amino group, a halogenated alkyl group, a hydroxyalkyl group, a carboxyl group or a carboxylate group.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 Carbon atoms, optimal The cycloalkyl-containing ring contains from 3 to 6 carbon atoms, most preferably a cyclopropyl group.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 , -C(O)NHR 7 , -NHC(O)R 7
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains from 3 to 10 ring atoms, more preferably the heterocyclyl ring contains from 5 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 , -C(O)NHR 7 , -NHC(O)R 7 , -
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, preferably a 6 to 10 membered aryl group, Phenyl and naphthyl are more preferred, and phenyl is most preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • Heteroaryl refers to a 5- to 14-membered all-carbon monocyclic or fused polycyclic group having a conjugated ⁇ -electron system, further comprising from 1 to 4 heteroatoms, wherein the heteroatoms are selected from one or more oxygen , sulfur or nitrogen. It is preferably a 5- to 10-membered heteroaryl group, more preferably a 5- to 6-membered heteroaryl group, even more preferably a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, or a pyridyl group.
  • heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -OR 7 , -C(O)OR 7 , -OC(O)R 7 , -O(CH 2 ) n C(O)OR 7 , -C(O)R 7 , -C (O) NHR 7, -NHC ( O) R 7, -NHC (O) oR 7, -NHS (O) m R 7, -NR 8 R 9,
  • Alkoxy means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and an alkane group.
  • Haloalkyl means that the alkyl group is substituted by one or more halogens, wherein the alkyl group is as defined above.
  • Hydrophilicity refers to an -OH group.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • R 7 to R 9 , m, n are as defined in the formula (I).
  • the compound of the formula (Ia) is reacted with N,N'-carbonyldiimidazole and aqueous ammonia under basic conditions to obtain a compound of the formula (Ib); the compound of the formula (Ib) and 2-cyanoacetic acid are The reaction is carried out under the conditions of methanesulfonyl chloride to obtain a compound of the formula (Ic); the compound of the formula (Ic) is subjected to ring formation under basic conditions to obtain a compound of the formula (Id); and the compound of the formula (Id) is reacted with an acetal to obtain a compound of the formula (Ie); a compound of the formula (Ie) is reacted with an amino protecting reagent to give a compound of the formula (If); a compound of the formula (If) is reduced under sodium borohydride to give a compound of the formula (Ig); The compound of the formula (Ig) is heated with a diethyl malonate to form a
  • R 1 to R 6 are as defined in the formula (I);
  • -OG is a leaving group, preferably a sulfonyloxy group
  • PG is selected from an alkyl or amino protecting group, wherein said amino protecting group is preferably a benzyl group, said alkyl or benzyl group being further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl Substituted by a heterocyclic group, a heteroaryl group or a substituent of -OR 7 ;
  • R 7 is as defined in the general formula (I).
  • the compound of the formula (IIa) is reacted with N,N'-carbonyldiimidazole under basic conditions to obtain a compound of the formula (IIb); the compound of the formula (IIb) and 2-cyanoacetic acid in methanesulfonate
  • the reaction is carried out under acid chloride conditions to obtain a compound of the formula (IIc); the compound of the formula (IIc) is cyclically reacted under basic conditions to obtain a compound of the formula (IId); and the compound of the formula (IId) is reacted with an acetal to give a formula (IIe) a compound; a compound of the formula (IIe) is reacted with an amino protecting reagent to give a compound of the formula (IIf); and a compound of the formula (IIf) is reduced under sodium borohydride to give a compound of the formula (IIg); IIg) Compound and diethyl malonate are heated and looped to obtain a compound of
  • R a , R b , R 1 , R 6 are as defined in the formula (II);
  • -OG is a leaving group, preferably a sulfonyloxy group
  • PG is selected from an alkyl or amino protecting group, wherein said amino protecting group is preferably a benzyl group, said alkyl or benzyl group being further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl Substituted by a heterocyclic group, a heteroaryl group or a substituent of -OR 7 ;
  • R 7 is as defined in the general formula (I).
  • the reagent for providing basic conditions includes an organic base and an inorganic base, and the organic base includes, but not limited to, triethylamine, pyridine, 2,6-lutidine, sodium methoxide, hexamethyl.
  • Lithium silicon hydride, sodium hexamethyldisilazide, n-butyl lithium, potassium t-butoxide or tetrabutylammonium bromide said inorganic bases including but not limited to sodium hydride, sodium carbonate, Sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide;
  • the nucleophilic substitution reaction in the process of the invention is preferably an inorganic base, more preferably sodium hydride or Barium carbonate;
  • the reagent for ring-opening reaction in the method of the present invention is preferably an inorganic base, more preferably lithium hydroxide or sodium hydride.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR chemical shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone System, D: ethyl acetate and dichloromethane system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and acetone System
  • D ethyl acetate and dichloromethane system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine
  • 2-Fluoro-4-iodoaniline 1a (50.80 g, 214 mmol) was dissolved in 254 mL of chloroform, triethylamine (60 mL, 429 mmol) was added, and then cooled to 0 ° C, and N,N'-carbonyldiimidazole (69.50) was added. g, 429 mmol), the reaction was stirred for 15 minutes, allowed to warm to room temperature and stirred for 4 hours. The temperature was lowered to 0 ° C, 254 mL of aqueous ammonia was added, and the mixture was filtered.
  • reaction mixture was concentrated under reduced vacuolulululululululululululululu -8-Methyl-2,4,7-tricarbonyl-pyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate 1j (4.13 g, yellow solid), yield: 37.1%.
  • EtOAc EtOAc m. 2-fluoro-4-iodophenyl-2,4,7-tricarbonyl-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yloxy tert-Butyl 2-methylphenyl)carbamate 2f (339 mg, brown liquid).
  • EtOAcjjjjjjjjjjj 4-(2-Fluoro-4-iodophenyl)-1-methyl-2-carbonyl-1,2-dihydropyridin-4-yloxy)-2-methylphenyl)carbamic acid tert-butyl ester 2 g (325 mg, brown solid).
  • the reaction mixture was concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielie
  • reaction mixture was extracted with methylene chloride (3 mL, EtOAc) 2-(2-Fluoro-4-iodophenylamino)-N-(4-methoxybenzyl)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxamide 3c (387 mg , light brown solid), the product was directly subjected to the next reaction without purification.
  • Phenylamino)-N-(4-methoxybenzyl)-1-methyl-4-(2-methyl-3-((tetrahydrofuran-3-yl)oxy)phenoxy)-6- Carbonyl-1,6-dihydropyridine-3-carboxamide 12d (140 mg, light brown solid).
  • the reaction mixture was concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielie
  • the crude product was 4-(3-chloro-2-methylphenoxy)-2-(2-fluoro-4-iodophenylamino)-N-(4-methoxybenzyl)-1-methyl-6 -carbonyl-1,6-dihydropyridine-3-carboxamide 14b (106 mg, 0.15 mmol) was dissolved in 5 mL of anisole, and aluminum chloride (100 mg, 0.75 mmol) was added thereto, the temperature was raised to 120 ° C, and the reaction was stirred for 3 hours. . The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.
  • the reaction mixture was concentrated under reduced pressure to give crystals crystals of crystals of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of
  • reaction mixture was concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielie
  • the reaction mixture was concentrated under reduced pressure to give crystals crystals of crystals of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of
  • reaction mixture was concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielie
  • the reaction mixture was concentrated under reduced pressure to give crystals crystals of crystals of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of
  • the reaction mixture was concentrated under reduced pressure to give crystals crystals of crystals of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of
  • EtOAc EtOAc EtOAc EtOAc 4-(3-Fluoro-2-methylphenoxy)-2-(2-fluoro-4-iodophenylamino)-N-((2,2-dimethyl-1,3-dioxocyclopentane) Alkyl-4-yl)methyl)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxamide 28f (139 mg,yield, brown solid).
  • 6-Methyl-3-hydroxy-pyridine (26 mg, 0.24 mmol) was dissolved in 5 mL of tetrahydrofuran, sodium hydride (12 mg, 0.30 mmol) was added, and the reaction was stirred for 2 hours, and 1-(2-fluoro-4-iodobenzene) was added.
  • 3-(4-methoxybenzyl)-8-methyl-2,4,7-tricarbonyl-pyrido[2,3-d]pyrimidin-5-yltrifluoromethanesulfonate 1j (136 mg, 0.20 mmol), the temperature was raised to 60 ° C, and the reaction was stirred for 1 hour.
  • Test Example 1 Determination of MEK1 kinase activity by the compound of the present invention
  • the in vitro MEK1 kinase activity was tested by the following method.
  • MEK kinase used in this experiment MEK 1 (Recombinant Human Protein, Invitrogen, Cat. No. PV3093).
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against MEK kinase, and the test compound is dissolved in dimethyl sulfoxide according to the concentration required for the experiment.
  • Prepare 1 ⁇ Buffer A Invitrogen, Cat. No. PV3189
  • dilute ATP with 1 ⁇ Buffer A to obtain 400 ⁇ M ATP solution
  • Z′-LYTE TM Ser/Thr 03Peptide Invitrogen, Cat. No. PV3200
  • MEK kinase (MEK 1) enzyme and 1 ⁇ Buffer A mixed appropriate amount of Z'-LYTE TM Ser/Thr 03phosphoPeptide substrate (Invitrogen, Cat. No.
  • test compound DMSO solution was prepared into 4% DMSO with 1 ⁇ buffer.
  • MEK 1 MEK kinase
  • the compounds of the present invention have a significant inhibitory effect on MEK 1 kinase activity.
  • Test Example 2 Determination of proliferation inhibition of MEK2 kinase by the compound of the present invention
  • the in vitro MEK2 kinase activity was tested by the following method.
  • MAPK1 (ERK2)Recombinant Human Protein (Invitrogen, Catalog No.PV3314)
  • the kit used in this experiment Z'-LYTE TM Kinase Assay Kit -Ser / Thr 03Peptide (Invitrogen, Product Number PV3176).
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against MEK kinase, and the test compound is dissolved in dimethyl sulfoxide according to the concentration required for the experiment.
  • Prepare 1 ⁇ Buffer A Invitrogen, Cat. No. PV3189
  • dilute ATP with 1 ⁇ Buffer A to obtain 400 ⁇ M ATP solution
  • Z′-LYTE TM Ser/Thr 03Peptide Invitrogen, Cat. No. PV3200
  • MEK kinase (MEK 2) enzyme, (ERK2) enzyme mixed with 1 ⁇ Buffer A appropriate amount of Z'-LYTE TM Ser/Thr 03phosphoPeptide substrate (Invitrogen, Cat. No.
  • MEK 2 MEK 2 biochemical inhibitory activity of the compound of the present invention was measured by the above test, and the IC 50 values measured are shown in Table 3.
  • the compounds of the present invention have a significant inhibitory effect on MEK 2 kinase activity.
  • Test Example 3 Determination of Proliferation Inhibition of Colo205 by Compounds of the Invention
  • the cell line used in this experiment was: Colo205 (Chinese Academy of Sciences Cell Bank, article number TCHu102).
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on a human colon cancer cell line, and its activity can be expressed by an IC 50 value.
  • the general protocol for such a test is as follows: First, the cell strain to be tested (purchased in the cell bank of the Chinese Academy of Sciences) is seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells/mL, and then the cells are subjected to a carbon dioxide incubator at 37 ° C. Incubate and allow them to grow overnight.
  • the medium is changed to a medium containing a series of concentration (10000 nM, 1000 nM, 100 nM, 10 nM, 1 nM, 0.1 nM) test compound solution, and the plate is returned to the incubator continuously. Cultivate for 72 hours. After 72 hours, the test compound was tested for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical). The IC 50 value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • Test Example 4 Inhibition of proliferation of human colon cancer cell line HCT116 by the compound of the present invention
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on human colon cancer cells, and its activity can be expressed by an IC 50 value.
  • the general protocol for such a test is as follows: First, the cell line to be tested is inoculated into a 384-well cell culture plate at a suitable cell concentration of 1000 cells/well, and then the cells are cultured in a 37 ° C, 5% carbon dioxide incubator to allow them to be cultured. Growing to overnight, the medium was changed to a medium supplemented with a series of concentration gradients (1000 nM, 250 nM, 62.50 nM, 15.63 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.06 nM, 0.015 nM, 0.004 nM) of the test compound solution. The plate was returned to the incubator for 72 hours.
  • concentration gradients 1000 nM, 250 nM, 62.50 nM, 15.63 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.06 nM, 0.015 nM, 0.004 nM
  • test compound was inhibited from cell proliferation activity by the method of CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical).
  • CCK8 Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical.
  • the IC 50 value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • Preferred compounds of the invention all have significant proliferation inhibitory activity against HCT116 cells.
  • Human liver microsome incubation system is used to reflect the activity of various enzymes through the production of metabolites.
  • the inhibition of the compounds on CYP1A2, CYP2C9, CYP2C6, CYP3A4m, CYP3A4t and CYP2C19 enzymes was examined, and the IC 50 value (concentration of the test compound when the enzyme activity was inhibited by 50%) was determined.
  • Example 1 Example 3, Example 4, Example 22, Example 29, Example 30 and Example 31 compound
  • liver microsome solution Human liver microparticles (20 mg/ml) were diluted to 0.25 mg/mL with PBS buffer.
  • test substance standard dilute to 50 mM with DMSO to obtain a stock solution I; dilute it to 100 ⁇ M with PBS, which is the liquid for incubation reaction.
  • the final concentrations of the above probe substrate and positive control inhibitor were prepared in PBS.
  • the above mixture was pre-incubated for 5 minutes at 37 °C. 40 ⁇ L of NADPH solution (2.5 mM in PBS) was added to the reaction mixture, and incubated at 37 ° C for 20 minutes. All samples were incubated for two samples. The reaction was stopped by adding 300 ⁇ L of ice-cold acetonitrile, and 100 ⁇ l of an internal standard was added thereto, followed by mixing. Centrifuge at 3500 rpm for 10 minutes. The supernatant was transferred to LC-MS/MS analysis.
  • NADPH solution 2.5 mM in PBS
  • IC 50 >10 ⁇ M is a weak inhibition
  • 1 ⁇ M ⁇ IC 50 ⁇ 10 ⁇ M is moderate inhibition
  • IC 50 ⁇ 1 ⁇ M is strongly inhibited.
  • Preferred compounds of the invention have a weaker inhibitory effect on CYP1A2, CYP2C9, CYP2C6, CYP3A4m, CYP3A4t and CYP2C19 enzymes, and thus the possibility of drug metabolic interactions is lower at clinical administration.
  • SD rats were used as test animals, and the drug concentrations in plasma at different times after administration of the compounds of Example 1, Example 22, Example 29 and Example 31 by intragastric administration were determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • Example 1 Example 22, Example 29 and Example 31 compounds
  • Healthy adult SD rats were divided into 4 groups, 4 in each group, half male and half female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.
  • mice Sixteen SD rats were divided into 4 groups, 4 in each group, half male and half female. After fasting overnight, they were intragastrically administered at a dose of 10 mg/kg and a dose of 10 ml/kg.
  • 0.1 ml of blood was collected from the eyelids before administration and 0.5, 1, 2, 4, 6, 8, 11, 24, 48 hours after administration, placed in heparinized tubes, centrifuged at 3500 rpm for 10 minutes, and plasma was separated, at -20 °C save. Eat 2 hours after administration.
  • the content of the test compound in the plasma of rats after intragastric administration was determined by LC/MS/MS.
  • the analytical method has a linear range of 1.00-2000 ng/ml and a lower limit of quantification of 1.00 ng/ml; the plasma sample is analyzed by pre-precipitation of the protein.
  • the compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect.

Abstract

本发明涉及吡啶酮类衍生物、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式（I）所示吡啶酮类衍生物及其可药用盐，其制备方法以及它们作为MEK抑制剂特别是作为癌症治疗剂的用途，其中通式（I）中的各取代基的定义与说明书中的定义相同。

Description

吡啶酮类衍生物、其制备方法及其在医药上的应用 技术领域
本发明涉及一种新型吡啶酮类衍生物及其可药用盐、其制备方法及含有该衍生物的药物组合物以及其作为MEK抑制剂特别是作为癌症治疗剂的用途。
背景技术
2008年，我国***的统计资料表明，每年我国新生肿瘤患者总数约为212.7万人左右，其中，有106万左右的恶性肿瘤新生患者；同时，全国约有268.5万左右的肿瘤现有患者，其中，恶性肿瘤现有患者约为148.5万左右。***部长陈竺在第21届世界抗癌大会发言中说，过去30年，中国癌症死亡率增加了80％，每年因此去世的有180万人，癌症已成中国居民的第一死因。根据《2012年中国卫生统计年鉴》统计调查数据显示，恶性肿瘤死亡率不断上升，前五位的恶性肿瘤类型有肺癌、肝癌、胃癌、食管癌及结直肠癌，其中肺癌和肝癌的死亡率上升最快，两者成为我国死亡率最高的恶性肿瘤疾病。
在过去的半个世纪中，针对肿瘤治疗的研究取得了多方面的进展。随着对肿瘤基因学和生物学研究的不断深入，多个细胞内肿瘤相关的关键信号通路被发现。肿瘤细胞依赖这些通路实现胞外信号的胞内转导，调节自身持续增殖和抗凋亡等活动，一方面维持其恶性表型特征，另一方面通过调节特定基因及其蛋白产物对治疗产生耐受。MAPKs激酶途径的异常与肿瘤的发生密切相关，由于其导致细胞增殖失控和分化阻滞，已成为肿瘤药物开发的优选靶标。
丝/苏氨酸促***原活化蛋白激酶(MAPKs,也称胞外信号调节激酶，ERKs)由酪氨酸激酶受体(如EGF受体)和/或G蛋白异源三聚体相关的细胞因子受体激活，可与多种由不同第二信使激起的胞内信号相互作用，磷酸化和调节各种酶及转录因子的活性(如NF-κB，Rsk 90，磷脂酶A2，c-Myc，CREB，Ets-1，AP-1及c-jun等)。在参与正常及异常细胞生长的MAPK途径中，Ras/Raf/MEK/Erk激酶途径是研究最为清楚也是最重要的途径之一。十多年前，科学家发现蛋白激酶家族Erks具有促增殖作用，随后的研究很快鉴定出Erk的上游激酶MEK家族，继而发现Raf可激活MEKs，其上游Ras属G蛋白，活化的GTP与Ras结合，间接激活Raf。大约30％的恶性肿瘤患者存在Ras基因突变，而在胰腺癌中，Ras基因突变率最高可达90％。B-Raf在黑色素瘤中的突变率高达50％-70％，在卵巢癌中达35％，在甲状腺癌中达30％，在结肠癌中达10％。MEKs也可被独立于Raf的激酶MEK激酶(也称MEKK)所激活。
MEKs也称MAP激酶激酶(MAPKK或Erk激酶)，属于双特异性激酶，可磷酸化MAPK(p44MAPK(Erk 1)及p42MAPK(Erk 2))的丝/苏氨酸残基和酪氨酸残基(Erk1 磷酸化位点为T202和Y204，Erk2磷酸化位点为T183和Y185)，MEK家族包含五种基因：MEK1,MEK2,MEK3,MEK4和MEK5。MEKs的N-端为负调控区，C-端的催化区具有与Erks结合并激活Erks的功能，实验发现，敲除MEK1的调控区会导致MEK1和Erk固有活性的抑制。
MEK1的分子量约为44kDa，共含393个氨基酸，主要表达于成人组织尤其是脑组织中，在胚胎发育期间也可检测到微量的MEK1表达。MEK1通过S218和S222位点的磷酸化来触发其活性，研究发现在NIH3T3细胞中，将这两个残基换成天冬氨酸或谷氨酸，其活性增加，集落的形成也增加。原代细胞培养中MEK1的固有活性促进细胞的衰老和p53与p16INK4a的表达，而在永生细胞和p53或p16INK4a缺失的细胞中，MEK1的作用正好相反。MEK2的分子量约45kDa，与MEK1具有79％的序列相似性，通过S222和S226位点的磷酸化来触发其活性。MEK1和MEK2对不同的MAPK亚型，Erk1和Erk2的磷酸化催化活性不同。MEK3,MEK4和MEK5不通过作用于Erks发挥其作用。
针对MAPK信号通路，目前已有多个特异性抑制Raf和MEK活性的化合物处于临床和上市阶段。其中sorafenib(Bay 43-9006)于2006年上市，属非特异性的丝/苏氨酸和酪氨酸激酶抑制剂，其作用靶点包含Raf,MEK,VEGFR2/3,Flt-3,PDGFR,c-Kit等。B-Raf特异性抑制剂如dabrafenib(GSK2118436)和vemurafenib(PLX4032)显示良好的临床效果，但持续时间并不长久，同时，临床研究发现，接受PLX4032有效治疗的患者，其症状大部分复发，提示B-Raf抑制剂的长期治疗会导致患者产生获得性耐药性，对B-Raf抑制剂不再敏感。为克服患者的耐药性，临床上常将MEK抑制剂与B-Raf抑制剂联用。特异性抑制MEK1/2抑制剂Trametinib(GSK-1120212)由GSK公司开发，现已进入预注册阶段，其它MEK1/2抑制剂Selumetinib(AZD-6422),Pimasertib hydrochloride(AS-703026),TAK-733等已进入临床试验阶段，但这些MEK抑制剂并无公布其与Erk1或Erk2的相互作用数据。
目前公开了一系列的MEK抑制剂的专利申请，其中包括WO2007096259、WO2010003022和WO2012162293等。
为了达到更好的肿瘤治疗效果的目的，更好的满足市场需求，我们希望能开发出新一代的高效低毒的针对MAPKs信号通路的抑制剂，特别是MEK靶点抑制剂。本发明将提供一种新型结构的MEK抑制剂，并发现具有此类结构的化合物CYP450抑制作用小，具有良好的活性，并表现出优异的抗肿瘤细胞增殖的作用。
发明内容
本发明的目的在于提供通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐：
Figure PCTCN2014085976-appb-000001
其中：
R1选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代；
R2或R3各自独立地选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、氰基、硝基、烯基、炔基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代；
R4选自芳基或杂芳基，其中所述的芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、氰基、羟基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代；
R5选自氢原子、烷基、烯基或炔基，其中所述的烷基、烯基或炔基各自独立地任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基或卤代烷基的取代基所取代；
R6选自氢原子、卤素或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、氰基、硝基、烷氧基、环烷基、杂环基、芳基或杂芳基的取代基所取代；
R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
R8或R9各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
或者，R8或R9与相连接的氮原子一起形成杂环基，其中所述的杂环基含有一个或多个N、O或S(O)m杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
m为0、1或2；并且
n为0、1或2。
在本发明一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R1选自芳基或杂芳基，其中所述的芳基或杂芳基任选进一步被一个或多个卤素、氰基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代，并且R7、R8、R9、m和n如通式(I)中所定义。
在本发明又一优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R1选自苯基或吡啶基，其中所述的苯基或吡啶基任选进一步被一个或多个选自烷基、卤素、卤代烷基、-OR7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、或-NHS(O)mR7的取代基所取代，并且R7和m如通式(I)中所定义。
在本发明又一优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R2选自氢原子，R3选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、烯基、炔基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代，并且R7、R8、R9、m和n如通式(I)中所定义。
在本发明又一优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R4为芳基，其中所述的芳基任选进一步被一个或多个卤素所取代。
在本发明又一优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R5为烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基或卤代烷基的取代基所取代。
在本发明又一优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R6选自氢原子或卤素。
在本发明又一优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐：
Figure PCTCN2014085976-appb-000002
Ra或Rb选自氢原子、卤素、烷基或卤代烷基；
R1选自苯基或吡啶基，其中所述的苯基或吡啶基任选进一步被一个或多个选自烷基、卤素、卤代烷基、-OR7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、或-NHS(O)mR7的取代基所取代；
R6选自氢原子、卤素或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、氰基、硝基、烷氧基、环烷基、杂环基、芳基或杂芳基的取代基所取代；并且
R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代。
在本发明又一优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R7选自氢原子、烷基、环烷基或杂环基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基的取代基所取代。
本发明典型的化合物包括，但不限于：
Figure PCTCN2014085976-appb-000003
Figure PCTCN2014085976-appb-000004
Figure PCTCN2014085976-appb-000005
Figure PCTCN2014085976-appb-000006
Figure PCTCN2014085976-appb-000007
Figure PCTCN2014085976-appb-000008
Figure PCTCN2014085976-appb-000009
Figure PCTCN2014085976-appb-000010
Figure PCTCN2014085976-appb-000011
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐。
本发明还提供一种通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，可用作合成通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体的中间体：
Figure PCTCN2014085976-appb-000012
其中：
R1、R4～R6的定义如通式(I)中所述；
PG选自烷基或氨基保护基，其中所述的氨基保护基优选为苄基，所述的烷基或苄基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、环烷基、杂环基、杂芳基或-OR7的取代基所取代；并且
R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代。
本发明通式(IA)的典型的化合物包括，但不限于：
Figure PCTCN2014085976-appb-000013
Figure PCTCN2014085976-appb-000014
Figure PCTCN2014085976-appb-000015
Figure PCTCN2014085976-appb-000016
Figure PCTCN2014085976-appb-000017
Figure PCTCN2014085976-appb-000018
Figure PCTCN2014085976-appb-000019
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐。
本发明还提供一种制备通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐的方法，该方法包括：
Figure PCTCN2014085976-appb-000020
将通式(Ii)与亲核试剂R1H反应得到通式(IA)化合物；
其中：R1、R4～R6的定义如通式(I)中所述；
-OG为离去基团，优选为磺酰氧基；
PG选自烷基或氨基保护基，其中所述的氨基保护基优选为苄基，所述的烷基或苄基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基或-OR7的取代基所取代；并且
R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤 素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
上述技术方案中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、2,6-二甲基吡啶、甲醇钠、六甲基二硅基胺基锂、六甲基二硅基胺基钠，正丁基锂、叔丁醇钾或四丁基溴化铵，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸铯、氢氧化锂、氢氧化钠或氢氧化钾；优选碱性条件的试剂为无机碱类，更优选氢化钠或碳酸铯。
本发明还提供一种制备通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐的方法，该方法包括：
Figure PCTCN2014085976-appb-000021
通式(IA)化合物在碱性条件下开环，任选进一步脱去氨基保护基PG，得到通式(I)化合物；
其中：
R1～R6的定义如通式(I)中所述；
PG选自烷基或氨基保护基，其中所述的氨基保护基优选为苄基，所述的烷基或苄基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基或-OR7的取代基所取代；并且
R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
上述技术方案中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、2,6-二甲基吡啶、甲醇钠、六甲基二硅基胺基锂、六甲基二硅基胺基钠，正丁基锂、叔丁醇钾或四丁基溴化铵，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸铯、氢氧化锂、氢氧化钠或氢氧化钾；本发明方法中开环反应优选碱性条件的试剂为无机碱类，更优选氢氧化锂、氢氧化钠或甲醇钠。
本发明进一步涉及一种药物组合物，其含有治疗有效量的本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及 其混合物形式，及其可药用盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物在制备抑制MEK的药物中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物在制备治疗炎性病症、自身免疫性疾病、心血管病症、增殖性疾病或感受伤害的病症的药物中的用途，其中所述的增殖性疾病可以为癌症(如下所定义)。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物在制备治疗癌症的药物中的用途，其中所述癌症选自黑色素瘤、脑瘤(具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(结肠癌、直肠癌等)、肺癌(非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(子***、子宫内膜癌等)、头颈肿瘤(上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤等)、真性红细胞增多症、白血病(急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物在制备治疗癌症的药物中的用途，其中所述癌症优选为结肠直肠癌或肺癌。
本发明还涉及一种抑制MEK活性的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物。
换言之，本发明涉及一种治疗炎性病症、自身免疫性疾病、心血管病症、增殖性疾病或感受伤害的病症的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物，其中所述的增殖性疾病可以为癌症(如下所定义)。
本发明进一步涉及一种治疗癌症的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物，其中所述癌症选自黑色素瘤、脑瘤(具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(结肠癌、直肠癌等)、肺癌(非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(子***、子宫内膜癌等)、头颈肿瘤(上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤等)、真性红细胞增多症、白血病(急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
本发明还涉及作为抑制MEK活性的药物的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物。
本发明还涉及作为治疗炎性病症、自身免疫性疾病、心血管病症、增殖性疾病或感受伤害的病症的药物的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物，其中所述的增殖性疾病可以为癌症(如下所定义)。
本发明进一步涉及作为治疗癌症的药物的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或包含其的药物组合物，其中所述癌症选自黑色素瘤、脑瘤(具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(结肠癌、直肠癌等)、肺癌(非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(子***、子宫内膜癌等)、头颈肿瘤(上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤等)、真性红细胞增多症、白血病(急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或***胶和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和***胶；分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油悬浮液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水可使适用于制备水混悬也的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单 油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
药物组合物可以是无菌注射水溶液形式。可在使用的可接受的溶媒和溶剂中有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、***的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明详述
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，更优选含有1至6个碳原子的烷基，最优选含有1至4个碳原子的烷基，最佳为甲基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二 甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。优选C2-10烯基，更优选C2-6烯基，最优选C2-4烯基。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
“炔基”指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。优选C2-10炔基，更优选C2-6炔基，最优选C2-4炔基。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子，最优 选环烷基环包含3至6个碳原子，最佳为环丙基。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子，更优选杂环基环包含3至10个环原子，更优选杂环基环包含5至6个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元的芳基，更优选苯基和萘基，最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2014085976-appb-000022
Figure PCTCN2014085976-appb-000023
和
Figure PCTCN2014085976-appb-000024
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、 -C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
“杂芳基”指具有共轭的π电子体系的5至14元全碳单环或稠合多环基团，进一步包含1至4个杂原子的，其中杂原子选自一个或多个氧、硫或氮。优选为5至10元的杂芳基，更优选为5元至6元的杂芳基，甚至更优选呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2014085976-appb-000025
Figure PCTCN2014085976-appb-000026
和
Figure PCTCN2014085976-appb-000027
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基、环烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自为烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
“卤代烷基”指烷基被一个或多个卤素取代，其中烷基的定义如上所述。
“羟基”指-OH基团。
“羟烷基”指被羟基取代的烷基，其中烷基的定义如上所述。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“氧代基”指＝O。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
R7～R9、m、n的定义如通式(I)中所述。
本发明的合成方法
为了完成本发明的合成目的，本发明采用如下的合成技术方案：
一种制备通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐的方法，该方法包括：
Figure PCTCN2014085976-appb-000028
合成方案1
冰浴下，通式(Ia)化合物在碱性条件下，与N,N’-羰基二咪唑和氨水反应，得到通式(Ib)化合物；通式(Ib)化合物与2-氰基乙酸在甲磺酰氯条件下反应，得到通式(Ic)化合物；通式(Ic)化合物在碱性条件下成环反应，得到通式(Id)化合物；通式(Id)化合物与缩醛反应，得到通式(Ie)化合物；通式(Ie)化合物与氨基保护试剂反应，得到通式(If)化合物；通式(If)化合物在硼氢化钠条件下还原，得到通式(Ig)化合物；通式(Ig)化合物与丙二酸二乙酯加热成环，通式(1h)化合物；通式(1h)化合物与羟基保护基反应，得到通式(1i)化合物；通式(1i)化合物与亲核试剂R1H反应，得到通式(IA)化合物；通式(IA)化合物在碱性条件下开环，任选进一步脱去氨基保护基PG，得到通式(I)化合物；
其中：R1～R6的定义如通式(I)中所述；
-OG为离去基团，优选为磺酰氧基；
PG选自烷基或氨基保护基，其中所述的氨基保护基优选为苄基，所述的烷基或苄基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、杂环基、杂芳基或-OR7的取代基所取代；
R7的定义如通式(I)中所述。
一种制备通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐的方法，该方法包括：
Figure PCTCN2014085976-appb-000029
合成方案二
冰浴下，通式(IIa)化合物在碱性条件下，与N,N’-羰基二咪唑反应，得到通式(IIb)化合物；通式(IIb)化合物与2-氰基乙酸在甲磺酰氯条件下反应，得到通式(IIc)化合物；通式(IIc)化合物在碱性条件下成环反应，得到通式(IId)化合物；通式(IId)化合物与缩醛反应，得到通式(IIe)化合物；通式(IIe)化合物与氨基保护试剂反应， 得到通式(IIf)化合物；通式(IIf)化合物在硼氢化钠条件下还原，得到通式(IIg)化合物；通式(IIg)化合物与丙二酸二乙酯加热并成环，得到通式(IIh)化合物；通式(IIh)化合物与羟基保护基反应，得到通式(IIi)化合物；通式(IIi)化合物与亲核试剂R1H反应，得到通式(IIA)化合物；通式(IIA)化合物在碱性条件下开环，任选进一步脱去氨基保护基PG，得到通式(II)化合物；
其中：Ra、Rb、R1、R6的定义如通式(II)中所述；
-OG为离去基团，优选为磺酰氧基；
PG选自烷基或氨基保护基，其中所述的氨基保护基优选为苄基，所述的烷基或苄基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、杂环基、杂芳基或-OR7的取代基所取代；
R7的定义如通式(I)中所述。
上述技术方案中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、2,6-二甲基吡啶、甲醇钠、六甲基二硅基胺基锂、六甲基二硅基胺基钠，正丁基锂、叔丁醇钾或四丁基溴化铵，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸铯、氢氧化锂、氢氧化钠或氢氧化钾；本发明方法中亲核取代反应优选碱性条件的试剂为无机碱类，更优选氢化钠或碳酸铯；本发明方法中开环反应优选碱性条件的试剂为无机碱类，更优选氢氧化锂或氢化钠。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR化学位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18150×4.6mm色谱柱)。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)，达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和丙酮体系，D：乙酸乙酯和二氯甲烷体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000030
第一步
1-(2-氟-4-碘苯基)脲
将2-氟-4-碘苯胺1a(50.80g，214mmol)溶解于254mL三氯甲烷中，加入三乙胺(60mL，429mmol)，降温至0℃，加入N,N'-羰基二咪唑(69.50g，429mmol)，搅拌反应15分钟，升至室温，搅拌反应4小时。降温至0℃，加入254mL氨水，过滤，滤饼依次用水(50mL×2)，三氯甲烷(20mL×2)，乙酸乙酯洗涤(50mL×2)，烘干，得到粗品标题产物1-(2-氟-4-碘苯基)脲1b(53g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):281.0[M+1]
第二步
2-氰基-N-((2-氟-4-碘苯基)氨基甲酰基)乙酰胺
将粗品1-(2-氟-4-碘苯基)脲1b(113g，404mmol)溶解于450mL N,N-二甲基甲酰胺中，加入2-氰基乙酸(41g，488mmol)，降温至0℃，加入甲磺酰氯(55.44g，484mmol)，升至室温，搅拌反应2小时。加入780mL水和异丙醇(V:V＝1:2)的混合溶液，再搅拌1小时。过滤，滤饼依次用水(200mL×2)，乙酸乙酯洗涤(50mL)， 烘干，得到粗品标题产物2-氰基-N-((2-氟-4-碘苯基)氨基甲酰基)乙酰胺1c(143g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):345.9[M-1]
第三步
6-氨基-1-(2-氟-4-碘苯基)嘧啶-2,4(1H,3H)-二酮
将粗品2-氰基-N-((2-氟-4-碘苯基)氨基甲酰基)乙酰胺1c(156g，430mmol)溶解于628mL水中，加入2M氢氧化钠溶液(22.6mL，42mmol)，加热至85℃，搅拌反应1小时。冷却至0℃，滴加2M盐酸至反应液pH为3，加入300mL异丙醇，过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(100mL×3)，烘干，得到粗品标题产物6-氨基-1-(2-氟-4-碘苯基)嘧啶-2,4(1H,3H)-二酮1d(128g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):348.0[M+1]
第四步
(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒
将粗品6-氨基-1-(2-氟-4-碘苯基)嘧啶-2,4(1H,3H)-二酮1d(128g，368.80mmol)溶解于250mL N,N-二甲基甲酰胺中，加入N,N-二甲基甲酰胺二甲基缩醛(124mL，935mmol)，搅拌反应4.5小时。加入720mL水和异丙醇(V:V＝5:1)的混合溶液，再搅拌1小时。过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(50mL×2)，烘干，得到粗品标题产物(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1e(132g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):403.0[M+1]
第五步
(E)-N'-(3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒
将粗品(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1e(20g，50mmol)溶解于150mL N,N-二甲基甲酰胺中，加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(22.4mL，150mmol)和4-甲氧基氯苄(14.1mL，104.30mmol)，升温至75℃，搅拌反应3小时。冷却至室温，加入675mL水和异丙醇(V:V＝2:1)的混合溶液，再搅拌1小时。过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(50mL×2)，烘干，得到粗品标题产物(E)-N'-(3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1f(35g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):523.0[M+1]
第六步
1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮
将硼氢化钠(3.80g，100mmol)溶解于210mL乙醇和叔丁醇(V:V＝1:2)的混合溶液中，加入粗品(E)-N'-(3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二羰基-1,2,3,6-四 氢嘧啶-4-基)-N,N-二甲基甲脒1f(35g，67mmol)，升温至65℃，搅拌反应1小时。冷却至0℃，加入175mL水，再加入140mL 10％柠檬酸，过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(50mL×2)，烘干，得到粗品标题产物1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮1g(33g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):482.0[M+1]
第七步
1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将粗品1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮1g(10.80g，22.44mmol)和丙二酸二乙酯(21.20g，157.09mmol)溶解于100mL苯醚中，升温至230℃，搅拌反应1小时。冷却至室温，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮1h(8.97g，橙黄色固体)，产率：72.9％。
MS m/z(ESI):550.0[M+1]
第八步
1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯
将1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮1h(8.97g，16.33mmol)溶解于100mL二氯甲烷中，加入三乙胺(7.00g，65.32mmol)，冷却至0℃，再加入三氟甲基磺酸酐(9.21g，32.66mmol)，升至室温，搅拌反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(4.13g，黄色固体)，产率：37.1％。
MS m/z(ESI):682.0[M+1]
第九步
5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将3-氟-2-甲基苯酚(30mg，0.24mmol)溶解于5mL四氢呋喃中，加入氢化钠(12mg，0.30mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮1k(131mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):658.1[M+1]
第十步
4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮1k(131mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝2:1)的混合溶液中，加入氢氧化锂(168mg，4mmol)，升温至40℃，搅拌反应0.5小时，降至室温，搅拌反应12小时。加入50mL二氯甲烷，有机相用饱和碳酸氢钠溶液洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺1m(126mg，棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):632.1[M+1]
第十一步
4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺1m(126mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应3.5小时。加入10mL水和1mL1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺1(33mg，浅棕色固体)，产率：32.3％。
MS m/z(ESI):512.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),7.60-7.66(m,3H),7.34-7.44(m,2H),7.18(t,1H),7.10(d,1H),6.67(t,1H),5.04(s,1H),3.15(s,3H),2.06(s,3H).
实施例2
N,1-二甲基-4-(3-(乙基磺酰氨基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000031
第一步
3-甲基-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将3-甲基-1-(2-氟-4-碘苯基)-6-(甲基氨基)嘧啶-2,4(1H,3H)-二酮2a(2.70g，7.19mmol，采用专利申请“WO2005/121142A1”公开的方法制备而得)和丙二酸二乙酯(8.07g，50.38mmol)溶解于24mL苯醚中，升温至230℃，搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-甲基-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮2b(2.20g，棕红色固体)，产率：68.9％。
MS m/z(ESI):444.1[M+1]
第二步
3,8-二甲基-1-(2-氟-4-碘苯基)-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基三氟甲基磺酸酯
将3-甲基-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮2b(2.20g，5mmol)溶解于20mL二氯甲烷中，加入三乙胺(2.14g，20mmol)，冷却至0℃，再加入三氟甲基磺酸酐(2.82g，10mmol)，升至室温，搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3,8-二甲基-1-(2-氟-4-碘苯基)-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基三氟甲基磺酸酯2c(1.50g，黄色固体)，产率：52.1％。
MS m/z(ESI):576.0[M+1]
第三步
(3-羟基-2-甲基苯基)氨基甲酸叔丁酯
将3-氨基-2-甲基苯酚2d(2g，16.20mmol)溶解于300mL二氯甲烷中，加入二碳酸二叔丁酯(4.25g，19.50mmol)，升温至70℃，搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(3-羟基-2-甲基苯基)氨基甲酸叔丁酯2e(3.0g，白色固体)，产率：83.1％。
MS m/z(ESI):222.2[M-1]
第四步
(3-(3,8-二甲基-1-(2-氟-4-碘苯基)-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧基)-2-甲基苯基)氨基甲酸叔丁酯
将(3-羟基-2-甲基苯基)氨基甲酸叔丁酯2e(120mg，0.52mmol)溶解于10mL四氢呋喃中，加入氢化钠(25mg，0.63mmol)，搅拌反应2小时，加入3,8-二甲基-1-(2-氟-4-碘苯基)-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基三氟甲基磺酸酯2c(300mg，0.53mmol)，升温至70℃，搅拌反应2小时。反应液减压浓缩，加入50mL乙酸乙酯和20mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(3-(3,8-二甲基-1-(2-氟-4-碘苯基)-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧基)-2-甲基苯基)氨基甲酸叔丁酯2f(339mg，褐色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):649.1[M+1]
第五步
(3-(5-甲基氨甲酰基-6-(2-氟-4-碘苯基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧基)-2-甲基苯基)氨基甲酸叔丁酯
将粗品(3-(3,8-二甲基-1-(2-氟-4-碘苯基)-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧基)-2-甲基苯基)氨基甲酸叔丁酯2f(339mg，0.52mmol)溶解于10mL四氢呋喃中，加入2mL水，加入氢氧化锂(218mg，5.20mmol)，升温至40℃，搅拌反应1.5小时。反应液减压浓缩，加入50mL乙酸乙酯，用水洗涤(10ml)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(3-(5-甲基氨甲酰基-6-(2-氟-4-碘苯基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧基)-2-甲基苯基)氨基甲酸叔丁酯2g(325mg，褐色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):623.0[M+1]
第六步
N,1-二甲基-4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(3-(5-甲基氨甲酰基-6-(2-氟-4-碘苯基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧基)-2-甲基苯基)氨基甲酸叔丁酯2g(325mg，0.52mmol)溶解于10mL二氯甲烷中，加入3ml三氟乙酸，搅拌反应1小时。反应液减压浓缩，加入100mL乙酸乙酯，有机相用饱和碳酸氢钠溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物N,1-二甲基-4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-6-羰基-1,6-二氢吡啶-3-甲酰胺2h(253mg，褐色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):522.9[M+1]
第七步
N,1-二甲基-4-(3-(乙基磺酰氨基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品N,1-二甲基-4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-6-羰基-1,6-二氢吡啶-3-甲酰胺2h(175mg，0.34mmol)溶解于10mL二氯甲烷中，加入2.5ml吡啶，降温至0℃，加入乙基磺酰氯(65mg，0.50mmol)，升至室温，搅拌反应12小时。加入100mL乙酸乙酯和30ml水，有机相用水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物N,1-二甲基-4-(3-(乙基磺酰氨基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺2(85mg，黄色固体)，产率：41.4％。
MS m/z(ESI):615.1[M+1]
1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),9.23(s,1H),8.03-8.07(m,1H),7.59-7.64(dd,1H),7.40-7.44(dd,1H),7.25-7.35(m,2H),7.07-7.10(dd,1H),6.67-6.72(t,1H),4.95(s,1H),3.22(s,3H),3.10-3.17(q,2H),2.50(s,3H),2.11(s,3H),1.25-1.29(t,3H).
实施例3
4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000032
第一步
(3-(1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧代)-2-甲基苯基)氨基甲酸叔丁酯
将(3-羟基-2-甲基苯基)氨基甲酸叔丁酯(165mg，0.74mmol)溶解于10mL四氢呋喃中，加入氢化钠(37mg，0.93mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(420mg，0.62mmol)，升温至60℃，搅拌反应0.5小时。反应液减压浓缩，得到粗品标题产物(3-(1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧代)-2-甲基苯基)氨基甲酸叔丁酯3a(465mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):755.1[M+1]
第二步
(3-(6-(2-氟-4-碘苯氨基)-5-(4-甲氧基苄基氨甲酰基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧代)-2-甲基苯基)氨基甲酸叔丁酯
将粗品(3-(1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧代)-2-甲基苯基)氨基甲酸叔丁酯3a(465mg，0.62mmol)溶解于12.5mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(517 mg，12.32mmol)，升温至40℃，搅拌反应1小时，降至室温，搅拌反应12小时。加入15mL水和50mL二氯甲烷，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(3-(6-(2-氟-4-碘苯氨基)-5-(4-甲氧基苄基氨甲酰基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧代)-2-甲基苯基)氨基甲酸叔丁酯3b(449mg，棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):729.2[M+1]
第三步
4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(3-(6-(2-氟-4-碘苯氨基)-5-(4-甲氧基苄基氨甲酰基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧代)-2-甲基苯基)氨基甲酸叔丁酯3b(449mg，0.62mmol)溶解于10mL二氯甲烷中，加入三氟醋酸(1.40g，12.32mmol)，搅拌反应2小时。反应液减压浓缩，加入10mL二氯甲烷和10mL饱和碳酸氢钠溶液，搅拌反应12小时。用二氯甲烷萃取反应液(30mL×2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3c(387mg，浅棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):629.0[M+1]
第四步
4-(3-(乙基甲磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3c(190mg，0.30mmol)溶解于10mL二氯甲烷和吡啶(V:V＝1:1)混合溶剂中，降温至0℃，加入乙基磺酰氯(42mg，0.33mmol)，升至室温，搅拌反应12小时。加入50mL二氯甲烷，有机相用水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3d(216mg，棕黑色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):720.9[M+1]
第五步
4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3d(200mg，0.28mmol)溶解于10mL苯甲醚中，加入氯化铝(185mg，1.39mmol)，升温至120℃，搅拌反应1小时。加入10mL水和1mL 1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥， 过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3(35mg，浅棕色固体)，产率：20.8％。
MS m/z(ESI):601.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),9.27(s,1H),7.58-7.68(m,3H),7.43(d,1H),7.27-7.35(m,2H),7.14(d,1H),6.67(t,1H),4.96(s,1H),3.14(s,3H),3.13(q,2H),2.12(s,3H),1.26(t,3H).
实施例4
4-(3-乙酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000033
第一步
4-(3-乙酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3c(190mg，0.30mmol)溶解于10mL二氯甲烷和吡啶(V:V＝1:1)混合溶剂中，降温至0℃，加入乙酰氯(26mg，0.33mmol)，升至室温，搅拌反应12小时。加入50mL二氯甲烷，有机相用水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-乙酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺4a(201mg，浅棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):671.1[M+1]
第二步
4-(3-乙酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-乙酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺4a(201mg，0.30mmol)溶解于10mL苯甲醚中，加入氯化铝(200mg，1.50mmol)，升温至120℃，搅拌反应0.5小时。反应液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-乙酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺4(30mg，棕色固体)，产率：18.2％。
MS m/z(ESI):551.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.89(s,1H),9.47(s,1H),7.58-7.68(m,3H),7.42(t,2H),7.29(t,1H),7.06(d,1H),6.67(t,1H),4.96(s,1H),3.14(s,3H),2.07(s,3H),2.02(s,3H).
实施例5
4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-5-氯-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000034
将4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3(30mg，0.05mmol)溶解于9mL二氯甲烷中，降温至0℃，加入3mL N-氯代丁二酰亚胺(7mg，0.05mmol)的二氯甲烷溶液，升温至40℃，搅拌反应12小时。反应液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-乙基磺酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-5-氯-6-羰基-1,6-二氢吡啶-3-甲酰胺5(19mg，白色固体)，产率：59.4％。
MS m/z(ESI):635.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.17(s,1H),8.96(s,1H),7.60(dd,1H),7.51(s,1H),7.36-7.46(m,2H),6.99-7.09(m,2H),6.74(t,1H),6.58(d,1H),3.36(s,3H),3.09(q,2H),2.30(s,3H),1.26(t,3H).
实施例6
4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-5-氟-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000035
将4-(3-(乙基磺酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3(12mg，0.02mmol)溶解于10mL二氯甲烷中，降温至0℃，加入3mL 1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(7mg，0.02mmol)的二氯甲烷溶液，升至室温，搅拌反应12小时。反应液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-乙基磺酰胺基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-5-氟-6-羰基-1,6-二氢吡啶-3-甲酰胺6(6mg，浅棕色固体)，产率：31.5％。
MS m/z(ESI):619.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.20(s,1H),8.68(s,1H),7.42-7.66(m,3H),7.30-7.40(m,1H),7.00-7.22(m,2H),6.78-7.88(m,1H),6.58-6.70(m,1H),3.33(s,3H),3.10(q,2H),2.28(s,3H),1.25(t,3H).
实施例7
4-(3-(环丙基甲酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000036
第一步
4-(3-(环丙基甲酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3c(126mg，0.20mmol)溶解于2mL二氯甲烷和吡啶(V:V＝1:1)混合溶剂中，降温至0℃，加入环丙基甲酰氯(23mg，0.22mmol)，升至室温，搅拌反应12小时。反应液减压浓缩，加入50mL二氯甲烷，有机相用水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-(环丙基甲酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺7a(139mg，浅棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):697.1[M+1]
第二步
4-(3-(环丙基甲酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-(环丙基甲酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺7a(139mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应1.5小时。加入10mL水和1mL 1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-(环丙基甲酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺7(49mg，浅棕色固体)，产率：42.6％。
MS m/z(ESI):577.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),9.70(s,1H),7.59-7.69(m,3H),7.38-7.46(m,2H),7.28(t,1H),7.05(d,1H),6.66(t,1H),4.96(s,1H),3.14(s,3H),2.01(s,3H),1.83-1.94(m,1H),0.75-0.83(m,4H).
实施例8
4-(3-(丙酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000037
第一步
4-(3-(丙酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-氨基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺3c(126mg，0.20mmol)溶解于2mL二氯甲烷和吡啶(V:V＝1:1)混合溶剂中，加入丙酰氯(20mg，0.22mmol)，搅拌反应12小时。反应液减压浓缩，加入30mL二氯甲烷，有机相用水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-(丙酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺8a(137mg，棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):685.1[M+1]
第二步
4-(3-(丙酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-(丙酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺8a(137mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应1.5小时。加入10mL水和1mL 1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤， 滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-(丙酰胺基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺8(55mg，浅棕色固体)，产率：48.7％。
MS m/z(ESI):565.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.89(s,1H),9.39(s,1H),7.59-7.69(m,3H),7.35-7.46(m,2H),7.29(t,1H),7.06(d,1H),6.66(t,1H),4.96(s,1H),3.14(s,3H),2.36(m,2H),1.99(s,3H),1.10(t,3H).
实施例9
(S)-2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000038
第一步
(S)-2-甲基-3-((四氢呋喃-3-基)氧基)苯酚
将甲磺酸(R)-四氢呋喃-3-基-酯9a(373mg，3mmol，采用公知的方法文献“Journal of Organic Chemistry,73(14),5397-5409；2008”制备而得)，2-甲基-1,3-二酚(500mg，3mmol)和碳酸铯(977mg，3mmol)溶解于10mL二甲基甲酰胺中，升温至80℃，搅拌反应12小时。加入10mL水和50mL乙酸乙酯，滴加1M盐酸至反应液pH为3，用二氯甲烷萃取(20mL×3)，合并有机相，用水洗涤(20mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(S)-2-甲基-3-((四氢呋喃-3-基)氧基)苯酚9b(290mg，褐色固体)，产率：49.8％。
MS m/z(ESI):195.1[M+1]
第二步
(S)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-(四氢呋喃-3-基氧代)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将(S)-2-甲基-3-((四氢呋喃-3-基)氧基)苯酚9b(290mg，1.49mmol)溶解于10mL四氢呋喃中，加入氢化钠(119mg，2.98mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(300mg，0.44mmol)，升温至60℃，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物(S)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮9c(319mg，浅黄色油状物)，产物不经纯化直接进行下一步反应。
第三步
(S)-2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(S)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮9c(319mg，0.44mmol)溶解于6mL四氢呋喃和水(V:V＝5:1)的混合溶液中，加入氢氧化锂(185mg，4.40mmol)，搅拌反应12小时。反应液减压浓缩，加入50mL乙酸乙酯和10mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(S)-2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺9d(130mg，灰色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):700.1[M+1]
第四步
(S)-2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(S)-2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺9d(130mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(124mg，0.93mmol)，升温至120℃，搅拌反应4小时。反应液减压浓缩，加入50mL乙酸乙酯和10mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物(S)-2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺9(50mg，浅棕色固体)，产率：46.5％。
MS m/z(ESI):580.1[M+1]
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.62-7.67(m,3H),7.42-7.44(d,1H),7.26-7.31(t,1H),6.93-6.96(d,1H),6.83-6.85(d,1H),6.64-6.69(t,1H),5.10(br,1H),5.00(s,1H),3.76-3.95(m,4H),3.15(s,3H),2.22-2.27(m,1H),2.19-2.03(m,4H).
实施例10
4-(2-甲基-3-(甲基氨甲酰基)苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000039
第一步
3-(1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧代)-2-甲基苯甲酸甲酯
将3-羟基-2-甲基-苯甲酸甲酯(122mg，0.73mmol，采用公知的方法文献“Tetrahedron Letters,48(31),5465-5469；2007”制备而得)溶解于10mL四氢呋喃中，加入氢化钠(60mg，1.50mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(500mg，0.73mmol)，升温至70℃，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物3-(1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧代)-2-甲基苯甲酸甲酯10a(509mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):698.1[M+1]
第二步
3-(6-(2-氟-4-碘苯氨基)-5-(4-甲氧基苄基氨甲酰基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧代)-2-甲基苯甲酸
将粗品3-(1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基氧代)-2-甲基苯甲酸甲酯10a(509mg，0.73mmol)溶解于24mL四氢呋喃和水(V:V＝5:1)的混合溶液中，加入氢氧化锂(308mg，7.34mmol)，搅拌反应12小时。加入10mL水和50mL乙酸乙酯，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物3-(6-(2-氟-4-碘苯氨基)-5-(4-甲氧基苄基氨甲酰基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧代)-2-甲基苯甲酸10b(500mg，黄色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):658.1[M+1]
第三步
4-(2-甲基-3-(甲基氨甲酰基)苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品3-(6-(2-氟-4-碘苯氨基)-5-(4-甲氧基苄基氨甲酰基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧代)-2-甲基苯甲酸10b(250mg，0.38mmol)溶解于5mL二甲基甲酰胺中，依次加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(146mg，0.76mmol)，1-羟基苯并三氮唑(103mg，0.76mmol)和0.5mL N,N-二异丙基乙胺，搅拌反应10分钟，再加入甲胺(0.2mL，0.38mmol)，搅拌反应12小时。加入20mL 10％的氯化锂和50mL乙酸乙酯，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-甲基-3-(甲基氨甲酰基)苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺10c(200mg，褐色固体)，产物不经纯化直接进行下一步反应。
第四步
4-(2-甲基-3-(甲基氨甲酰基)苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2-甲基-3-(甲基氨甲酰基)苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺10c(200mg，0.30mmol)溶解于5mL苯甲醚中，加入氯化铝(200mg，1.50mmol)，升温至120℃，搅拌反应3小时。反应液减压浓缩，加入50mL乙酸乙酯和15mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2-甲基-3-(甲基氨甲酰基)苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺10(35mg，白色固体)，产率：21.3％。
MS m/z(ESI):551.1[M+1]
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.31-8.33(m,1H),7.63-7.67(m,3H),7.27-7.45(m,4H),6.65-6.70(t,1H),5.01(s,1H),3.15(s,3H),2.76-2.78(d,3H),2.12(s,3H).
实施例11
4-(3-(环丙基氨甲酰基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000040
第一步
4-(3-(环丙基氨甲酰基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品3-(6-(2-氟-4-碘苯氨基)-5-(4-甲氧基苄基氨甲酰基)-1-甲基-2-羰基-1,2-二氢吡啶-4-基氧代)-2-甲基苯甲酸10b(250mg，0.38mmol)溶解于5mL二甲基甲酰胺中，依次加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(146mg，0.76mmol)，1-羟基苯并三氮唑(103mg，0.76mmol)和0.5mL N’,N’-二异丙基乙胺，搅拌反应10分钟，再加入环丙基甲胺(22mg，0.38mmol)，搅拌反应12小时。加入20mL 10％的氯化锂和50mL乙酸乙酯，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-(环丙基氨甲酰基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺11a(130mg，褐色固体)，产物不经纯化直接进行下一步反应。
第二步
4-(3-(环丙基氨甲酰基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-(环丙基氨甲酰基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺11a(130mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应3小时。反应液减压浓缩，加入50mL乙酸乙酯和15mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-(环丙基氨甲酰基)-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺11(40mg，褐色固体)，产率：35.4％。
MS m/z(ESI):577.1[M+1]
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.43-8.45(d,1H),7.63-7.67(m,3H),7.24-7.45(m,4H),6.65-6.70(t,1H),5.01(s,1H),3.15(s,3H),2.83-2.84(m,1H),2.11(s,3H),0.68-0.71(m,2H),0.52-0.54(m,2H).
实施例12
(R)-2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000041
第一步
(R)-2-甲基-3-((四氢呋喃-3-基)氧基)苯酚
将甲磺酸(S)-四氢呋喃-3-基-酯12a(1.65g，9.93mmol，采用公知的方法文献“Journal of Organic Chemistry,73(14),5397-5409；2008”制备而得)，2-甲基-1,3-二酚(2.46g，19.90mmol)和碳酸铯(3.23g，9.93mmol)溶解于250mL二甲基甲酰胺中，升温至80℃，搅拌反应12小时。滴加1M盐酸至反应液pH为7，用二氯甲烷萃取(100mL×3)，合并有机相，用水洗涤(100mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(R)-2-甲基-3-((四氢呋喃-3-基)氧基)苯酚12b(1.03g，类白色固体)，产率：53.3％。
MS m/z(ESI):195.1[M+1]
第二步
(R)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将(R)-2-甲基-3-((四氢呋喃-3-基)氧基)苯酚12b(47mg，0.24mmol)溶解于5mL四氢呋喃中，加入氢化钠(12mg，0.30mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物(R)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮12c(145mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第三步
(R)-2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(R)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮12c(145mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(168mg，4mmol)，升温至40℃，搅拌反应1小时。加入10mL水，用二氯甲烷萃取(10mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(R)-2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺12d(140mg，浅棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):700.0[M+1]
第四步
(R)-2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(R)-2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺12d(140mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应3.5小时。加入10mL水和1mL 1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物(R)-2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基-3-((四氢呋喃-3-基)氧基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺12(35mg，浅棕色固体)，产率：30.1％。
MS m/z(ESI):580.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.89(s,1H),7.59-7.69(m,3H),7.40-7.47(m,1H),7.29(t,1H),6.95(d,1H),6.84(d,1H),6.67(t,1H),5.07-5.13(m,1H),4.99(s,1H),3.75-3.95(m,4H),3.13(s,3H),2.19-2.29(m,1H),1.97-2.04(m,1H),1.95(s,3H).
实施例13
4-(3-乙酰基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000042
第一步
2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯酚
将1-(3-羟基-2-甲基苯)乙酮13a(3g，20mmol，采用公知的方法文献“Journal of Medicinal Chemistry,52(20),6433-6446；2009”制备而得)和30mL乙二醇溶解于30mL甲苯中，回流搅拌反应3.5小时。加入200mL乙酸乙酯，用水洗涤(100mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯酚13b(1.03g，白色固体)，产率：54.1％。
MS m/z(ESI):195.1[M+1]
第二步
1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯酚13b(47mg，0.24mmol)溶解于5mL四氢呋喃中，加入氢化钠(12mg，0.30mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮13c(145mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):726.2[M+1]
第三步
2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-5-(2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯氧基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮13c(145mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(168mg，4mmol)，升温至40℃，搅拌反应1小时。加入50mL乙酸乙酯，用水洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺13d(140mg，浅棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):700.1[M+1]
第四步
4-(3-乙酰基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品2-(2-氟-4-碘苯基氨基)-N-(4-甲氧基苄基)-1-甲基-4-(2-甲基-3-(2-甲基-1,3-二氧戊烷-2-基)苯氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺13d(140mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应3.5小时。加入10mL水和1mL 1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-乙酰基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺13(7mg，浅棕色固体)，产率：6.5％。
MS m/z(ESI):536.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.87(s,1H),7.74-7.78(m,1H),7.59-7.69(m,3H),7.39-7.49(m,3H),6.67(t,1H),4.95(s,1H),3.14(s,3H),2.60(s,3H),2.19(s,3H).
实施例14
4-(3-氯-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000043
第一步
5-(3-氯-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将3-氯-2-甲基-苯酚(26mg，0.18mmol)溶解于5mL四氢呋喃中，加入氢化钠(9mg，0.23mmol)，搅拌反应1小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(102mg，0.15mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(3-氯-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮14a(100mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):674.0[M+1]
第二步
4-(3-氯-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(3-氯-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮14a(100mg，0.15mmol)溶解于6mL四氢呋喃和水(V:V＝5:1)的混合溶液中，加入氢氧化锂(31mg，0.75mmol)，搅拌反应12小时。加入10mL水和50mL乙酸乙酯，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-氯-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺14b(106mg，黄棕色油状物)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):648.0[M+1]
第三步
4-(3-氯-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-氯-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺14b(106mg，0.15mmol)溶解于5mL苯甲醚中，加入氯化铝(100mg，0.75mmol)，升温至120℃，搅拌反应3小时。反应液减压浓缩，加入50mL乙酸乙酯和15mL水，有机相用1M的盐酸洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-氯-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺14(21mg，白色固体)，产率：26.5％。
MS m/z(ESI):528.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.79(s,1H),7.60-7.68(m,3H),7.41-7.47(m,2H),7.36(t,1H),7.23(d,1H),6.67(t,1H),5.00(s,1H),3.15(s,3H),2.18(s,3H).
实施例15
4-(2-氯-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000044
第一步
5-(2-氯-4-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2-氯-4-甲基-苯酚(34mg，0.24mmol)溶解于5mL四氢呋喃中，加入氢化钠(12mg，0.30mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(2-氯-4-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮15a(135mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):674.0[M+1]
第二步
4-(2-氯-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2-氯-4-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮15a(135mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(168mg，4mmol)，升温至40℃，搅拌反应1小时。加入50mL乙酸乙酯，有机相用1M的氢氧化钠溶液洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-氯-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺15b(130mg，黄棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):648.1[M+1]
第三步
4-(2-氯-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2-氯-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺15b(130mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应1.5小时。加入10mL水和1mL1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2-氯-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺15(50mg，灰白色固体)，产率：47.2％。
MS m/z(ESI):528.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.95(s,1H),7.62-7.71(m,2H),7.52-7.58(m,1H),7.48-7.52(m,1H),7.44(d,1H),7.87(d,1H),7.26-7.34(m,1H),6.67(t,1H),4.97(s,1H),3.14(s,3H),2.35(s,3H).
实施例16
4-(3-甲氧基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000045
第一步
5-(3-甲氧基-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将3-甲氧基-2-甲基-苯酚(27mg，0.19mmol)溶解于5mL四氢呋喃中，加入氢化钠(7mg，0.29mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(130mg，0.19mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物5-(3-甲氧基-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮16a(127mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(3-甲氧基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(3-甲氧基-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮16a(127mg，0.19mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(80mg，1.91mmol)，搅拌反应12小时。加入50mL乙酸乙酯，有机相用1M的氢氧化钠溶液洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-甲氧基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺16b(170mg，褐色油状物)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):644.1[M+1]
第三步
4-(3-甲氧基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-甲氧基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺16b(170mg，0.19mmol)溶解于5mL苯甲醚中，加入氯化铝(127mg，0.95mmol)，升温至120℃，搅拌反应1.5小时。加入10mL水和1mL 1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-甲氧基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺16(28mg，灰白色固体)，产率：28.0％。
MS m/z(ESI):524.1[M+1]
1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),7.61-7.67(m,3H),7.42-7.44(d,1H),7.28-7.33(t,1H),6.95-6.98(d,1H),6.82-6.85(d,1H),6.64-6.69(t,1H),4.99(s,1H),3.85(s,3H),3.14(s,3H),1.97(s,3H).
实施例17
4-(2-氟-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000046
第一步
5-(2-氟-4-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2-氟-4-甲基-苯酚(33mg，0.26mmol)溶解于5mL四氢呋喃中，加入氢化钠(16mg，0.40mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(2-氟-4-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮17a(131mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):658.0[M+1]
第二步
4-(2-氟-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2-氟-4-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮17a(131mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(42mg，1mmol)，搅拌反应4小时。加入50mL乙酸乙酯，有机相依次用水(30mL×1)，0.5M的盐酸(30mL×1)和饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-氟-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺17b(126mg，棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):632.0[M+1]
第三步
4-(2-氟-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2-氟-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺17b(126mg，0.20mmol)溶解于3mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至100℃，搅拌反应1小时。加入60mL二氯甲烷，有机相依次用水(50mL×2)和饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2-氟-4-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺17(32mg，类白色固体)，产率：31.4％。
MS m/z(ESI):512.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.84(s,1H),7.61-7.66(m,3H),7.41-7.43(m,1H),7.28-7.34(m,2H),7.12-7.15(m,1H),6.64-6.68(m,1H),5.10(s,1H),3.15(s,3H),2.36(s,3H).
实施例18
4-(2,3-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000047
第一步
5-(2,3-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2,3-二甲基-苯酚(24mg，0.19mmol)溶解于5mL四氢呋喃中，加入氢化钠(7mg，0.29mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(130mg，0.19mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(2,3-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮18a(125mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(2,3-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2,3-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮18a(125mg，0.19mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(80mg，1.91mmol)，搅拌反应2小时。加入50mL乙酸乙酯，有机相用1M的氢氧化钠溶液洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2,3-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺18b(130mg，黄色油状物)，产物不经纯化直接进行下一步反应。
第三步
4-(2,3-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2,3-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺18b(130mg，0.19mmol)溶解于5mL苯甲醚中，加入氯化铝(127mg，0.95mmol)，升温至120℃，搅拌反应1.5小时。加入10mL水和 1mL 1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2,3-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺18(26mg，白色固体)，产率：28.9％。
MS m/z(ESI):506.0[M-1]
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),7.63-7.67(m,3H),7.42-7.44(d,1H),7.15-7.22(m,2H),7.04-7.06(d,1H),6.64-6.69(t,1H),4.95(s,1H),3.14(s,3H),2.31(s,3H),2.04(s,3H).
实施例19
4-(2-氟-3-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000048
第一步
5-(2-氟-3-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2-氟-3-甲基苯酚(30mg，0.24mmol)溶解于5mL四氢呋喃中，加入氢化钠(12mg，0.30mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物5-(2-氟-3-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮19a(131mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):658.1[M+1]
第二步
4-(2-氟-3-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2-氟-3-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮19a(131mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(168mg，4mmol)，升温至40℃，搅拌反应1小时。加入50mL乙酸乙酯，有机相用1M的氢氧化钠溶液洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-氟-3-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺19b(126mg，浅棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):632.1[M+1]
第三步
4-(2-氟-3-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2-氟-3-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺19b(126mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应1.5小时。加入10mL水和1mL1M盐酸，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2-氟-3-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺19(35mg，灰白色固体)，产率：34.3％。
MS m/z(ESI):512.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),7.60-7.66(m,3H),7.40-7.46(m,1H),7.18-7.29(m,3H),6.67(t,1H),5.11(s,1H),3.14(s,3H),2.30(s,3H).
实施例20
4-(2,4-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000049
第一步
5-(2,4-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2,4-二甲基-苯酚(32mg，0.26mmol)溶解于5mL四氢呋喃中，加入氢化钠(16mg，0.40mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(2,4-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮20a(130mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(2,4-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2,4-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮20a(130mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(42mg，1mmol)，搅拌反应4小时。加入50mL乙酸乙酯，有机相依次用水(30mL×1)，0.5M的盐酸(30mL×1)和饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2,4-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺20b(124mg，红棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):628.1[M+1]
第三步
4-(2,4-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2,4-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺20b(124mg，0.20mmol)溶解于3mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至100℃，搅拌反应1小时。加入60mL二氯甲烷，有机相依次用水(50mL×2)和饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2,4-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺20(15mg，白色固体)，产率：31.4％。
MS m/z(ESI):508.1[M+1]
1H NMR(400MHz,DMSO-d6):δ10.0(s,1H),7.61-7.66(m,3H),7.41-7.44(m,1H),7.17-7.18(m,1H),7.07-7.14(m,2H),6.64-6.68(m,1H),4.96(s,1H),3.13(s,3H),2.31(s,3H),2.10(s,3H).
实施例21
4-(2,6-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000050
第一步
5-(2,6-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2,6-二甲基-苯酚(32mg，0.26mmol)溶解于5mL四氢呋喃中，加入氢化钠(16mg，0.40mmol)，搅拌反应1.5小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(2,6-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮21a(130mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(2,6-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二
氢吡啶-3-甲酰胺
将粗品5-(2,6-二甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮21a(130mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(42mg，1mmol)，搅拌反应4小时。加入70mL二氯甲烷，有机相依次用水(30mL×1)和饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2,6-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺21b(125mg，红棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):628.1[M+1]
第三步
4-(2,6-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2,6-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺21b(125mg，0.20mmol)溶解于3mL苯甲醚中，加入 氯化铝(133mg，1mmol)，升温至100℃，搅拌反应1.5小时。加入60mL二氯甲烷，有机相依次用水(50mL×2)和饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2,6-二甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺21(10mg，白色固体)，产率：9.9％。
MS m/z(ESI):508.1[M+1]
1H NMR(400MHz,DMSO-d6):δ10.33(s,1H),7.62-7.67(m,3H),7.42-7.44(m,1H),7.16-7.21(m,3H),6.69-6.74(m,1H),4.88(s,1H),3.12(s,3H),2.13(s,6H).
实施例22
4-(4-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000051
第一步
5-(4-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将4-氟-2-甲基苯酚(24mg，0.19mmol)溶解于5mL四氢呋喃中，加入氢化钠(7mg，0.29mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(130mg，0.19mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(4-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮22a(124mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(4-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(4-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮22a(124mg，0.19mmol)溶解于6mL四氢呋喃 和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(80mg，1.91mmol)，搅拌反应2小时。加入50mL乙酸乙酯和10mL水，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(4-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺22b(150mg，黄色油状物)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):630.1[M-1]
第三步
4-(4-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(4-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺22b(150mg，0.19mmol)溶解于5mL苯甲醚中，加入氯化铝(127mg，0.95mmol)，升温至120℃，搅拌反应1.5小时。加入20mL二氯甲烷和5mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(4-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺22(26mg，白色固体)，产率：26.6％。
MS m/z(ESI):510.0[M-1]
1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),7.63-7.67(m,3H),7.42-7.45(d,1H),7.26-7.30(m,2H),7.16-7.20(m,1H),6.64-6.70(t,1H),4.99(s,1H),3.15(s,3H),2.15(s,3H).
实施例23
4-(2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000052
第一步
5-(2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2-甲基苯酚(21mg，0.19mmol)溶解于5mL四氢呋喃中，加入氢化钠(7mg，0.29mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7- 三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(130mg，0.19mmol)，搅拌反应3小时。反应液减压浓缩，得到粗品标题产物5-(2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮23a(122mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮23a(122mg，0.19mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(80mg，1.91mmol)，搅拌反应2小时。加入50mL乙酸乙酯和10mL水，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺23b(140mg，黄色油状物)，产物不经纯化直接进行下一步反应。
第三步
4-(2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺23b(150mg，0.19mmol)溶解于5mL苯甲醚中，加入氯化铝(127mg，0.95mmol)，升温至120℃，搅拌反应1.5小时。加入20mL二氯甲烷和5mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺23(29mg，白色固体)，产率：30.9％。
MS m/z(ESI):492.0[M-1]
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.64-7.67(m,3H),7.21-7.45(m,5H),6.65-6.70(t,1H),4.97(s,1H),3.14(s,3H),2.15(s,3H).
实施例24
4-(3-羟基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000053
第一步
5-(3-羟基-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将3-羟基-2-甲基苯酚(24mg，0.19mmol)溶解于5mL四氢呋喃中，加入氢化钠(7mg，0.29mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(130mg，0.19mmol)，搅拌反应3小时。反应液减压浓缩，得到粗品标题产物5-(3-羟基-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮24a(125mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):656.0[M+1]
第二步
4-(3-羟基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(3-羟基-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮24a(125mg，0.19mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(80mg，1.91mmol)，搅拌反应12小时。加入50mL乙酸乙酯和10mL水，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-羟基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺24b(140mg，褐色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):629.9[M+1]
第三步
4-(3-羟基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(3-羟基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺24b(140mg，0.19mmol)溶解于5mL苯甲醚中，加入氯化铝(127mg，0.95mmol)，升温至100℃，搅拌反应3小时。加入20mL乙酸乙酯和5mL水，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(3-羟基-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺24(15mg，灰色固体)，产率：15.4％。
MS m/z(ESI):508.1[M-1]
1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.80(s,1H),7.59-7.67(m,3H),7.42-7.44(d,1H),7.09-7.14(t,1H),6.78-6.81(d,1H),6.64-6.69(m,2H),5.01(s,1H),3.14(s,3H),1.93(s,3H).
实施例25
4-(5-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000054
第一步
5-(5-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将5-氟-2-甲基-苯酚(33mg，0.26mmol)溶解于5mL四氢呋喃中，加入氢化钠(16mg，0.40mmol)，搅拌反应1小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(5-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮25a(131mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(5-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(5-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮25a(131mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(42mg，1mmol)，搅拌反应3小时。加入60mL乙酸乙酯，有机相依次用水(30mL×1)和饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(5-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺25b(126mg，棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):632.1[M+1]
第三步
4-(5-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(5-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺25b(126mg，0.20mmol)溶解于3mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至100℃，搅拌反应1小时。加入40mL二氯甲烷，有机相依次用水(50mL×2)和饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物4-(5-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺25(10mg，淡棕色固体)，产率：23.5％。
MS m/z(ESI):512.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),7.61-7.66(m,3H),7.40-7.44(m,2H),7.18-7.21(m,1H),7.10-7.15(m,1H),6.64-6.69(m,1H),5.03(s,1H),3.15(s,3H),2.11(s,3H).
实施例26
5-氟-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-酮-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000056
将4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-酮-1,6-二氢吡啶-3-甲酰胺1(10mg，0.02mmol)溶解于6mL二氯甲烷中，冷却至0℃，加入5mL 1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(11mg，0.03mmol)的二氯甲烷溶液，升至室温，搅拌反应12小时。反应液减压浓缩，用制备分离法纯化所得残余物，得到标题产物5-氟-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-酮-1,6-二氢吡啶-3-甲酰胺26(3mg，红棕色固体)，产率：30.0％。
MS m/z(ESI):530.1[M+1]
1H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.54-7.60(m,2H),7.44-7.46(m,1H),7.35-7.37(m,1H),7.14-7.20(m,1H),6.93-6.97(m,1H),6.76-6.78(m,1H),6.62-6.66(m,1H),3.33(s,3H),2.21(s,3H).
实施例27
(R)-N-(2,3-二羟基丙基)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000057
第一步
(R,E)-N'-(3-(2-氟-4-碘苯基)-1-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒
将粗品(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1e(3.30g，8.20mmol)，(R)-4-氯甲基-2,2-二甲基-1,3-二氧环戊烷(2.47g，16.40mmol)，碳酸铯(5.34g，16.40mmol)和碘化钾(200mg，1.20mmol)溶解于33mL N,N-二甲基甲酰胺中，升温至100℃，搅拌反应12小时。冷却至室温，加入200mL乙酸乙酯，有机相用水洗涤(100mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(R,E)-N'-(3-(2-氟-4-碘苯基)-1-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒27a(3.56g，黑棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):517.0[M+1]
第二步
(R)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮
将硼氢化钠(391mg，10.34mmol)溶解于15mL乙醇和叔丁醇(V:V＝1:2)的混合溶液中，冷却至0℃，加入15mL粗品(R,E)-N'-(3-(2-氟-4-碘苯基)-1-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒27a(3.56g，6.90mmol)的甲醇溶液，搅拌反应1小时，升至室温，搅拌反应12小时。冷却至0℃，加入100mL水，有机相用水洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(R)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮27b(3.16g，棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):476.0[M+1]
第三步
(R)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将粗品(R)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮27b(3.16g，6.65mmol)溶解于35mL丙二酸二乙酯中，回流搅拌反应1小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(R)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮27c(356mg，黄色固体)，产率：9.86％。
MS m/z(ESI):544.0[M+1]
第四步
(R)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯
将(R)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮27c(356mg，0.66mmol)溶解于5mL二氯甲烷中，加入三乙胺(281mg，2.62mmol)，冷却至0℃，再加入三氟甲基磺酸酐(370mg，1.31mmol)，升至室温，搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(R)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯27d(150mg，浅黄色固体)，产率：33.9％。
MS m/z(ESI):693.1[M+18]
第五步
(R)-5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将3-氟-2-甲基苯酚(34mg，0.27mmol)溶解于5mL四氢呋喃中，加入氢化钠(13mg，0.33mmol)，搅拌反应2小时，加入(R)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯27d(150mg，0.22mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物(R)-5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮27e(145mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第六步
(R)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(R)-5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮27e(145mg，0.22mmol)溶解于6mL四氢呋喃和水(V:V＝2:1)的混合溶液中，加入氢氧化锂(186mg，4.44mmol)，升温至40℃，搅拌反应1小时。加入20mL乙酸乙酯，有机相依次用饱和碳酸氢钠溶液(10mL×3)和水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(R)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺27f(139mg，红棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):626.1[M+1]
第七步
(R)-N-(2,3-二羟基丙基)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(R)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺27f(139mg，0.22mmol)溶解于10mL四氢呋喃中，加入5mL 1M盐酸，搅拌反应4小时。反应液减压浓 缩，用制备分离法纯化所得残余物，得到标题产物(R)-N-(2,3-二羟基丙基)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺27(70mg，浅棕色固体)，产率：53.8％。
MS m/z(ESI):586.2[M+1]
1H NMR(400MHz,DMSO-d6):δ9.33(s,1H),8.09(t,1H),7.61(d,1H),7.33-7.42(m,2H),7.17(t,1H),7.06(d,1H),6.69(t,1H),5.04(s,1H),3.39-3.46(m,1H),3.11-3.24(m,3H),3.19(s,3H),2.93-3.00(m,1H),2.06(s,3H).
实施例28
(S)-N-(2,3-二羟基丙基)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000058
第一步
(S,E)-N'-(3-(2-氟-4-碘苯基)-1-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒
将粗品(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1e(3.30g，8.20mmol)，(S)-4-氯甲基-2,2-二甲基-1,3-二氧环戊烷(2.47g，16.40mmol)，碳酸铯(5.34g，16.40mmol)和碘化钾(200mg，1.20mmol)溶解于33mL N,N-二甲基甲酰胺中，升温至100℃，搅拌反应12小时。冷却至室温，加入200mL乙酸乙酯，有机相用水洗涤(100mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(S,E)-N'-(3-(2-氟-4-碘苯基)-1-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒28a(3.80g，黑棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):517.0[M+1]
第二步
(S)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮
将硼氢化钠(418mg，11.04mmol)溶解于15mL乙醇和叔丁醇(V:V＝1:2)的混合溶液中，冷却至0℃，加入15mL粗品(S,E)-N'-(3-(2-氟-4-碘苯基)-1-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒28a(3.80g，7.36mmol)的甲醇溶液，搅拌反应1小时，升至室温，搅拌反应12小时。冷却至0℃，加入100mL水，有机相用水洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(S)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮28b(3.35g，棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):476.1[M+1]
第三步
(S)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将粗品(S)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮28b(3.35g，7.05mmol)溶解于35mL丙二酸二乙酯中，回流搅拌反应1小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(S)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮28c(300mg，黄色固体)，产率：7.83％。
MS m/z(ESI):544.0[M+1]
第四步
(S)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯
将(S)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮28c(300mg，0.55mmol)溶解于5mL二氯甲烷中，加入2,6-二甲基吡啶(237mg，2.21mmol)，冷却至0℃，再加入三氟甲基磺酸酐(311mg，1.10mmol)，升至室温，搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(S)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯28d(150mg，浅黄色固体)，产率：40.2％。
MS m/z(ESI):676.1[M+1]
第五步
(S)-5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将3-氟-2-甲基苯酚(34mg，0.27mmol)溶解于5mL四氢呋喃中，加入氢化钠(13mg，0.33mmol)，搅拌反应2小时，加入(S)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯28d(150mg，0.22mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物(S)-5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮28e(145mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第六步
(S)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(S)-5-(3-氟-2-甲基苯氧基)-1-(2-氟-4-碘苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮28e(145mg，0.22mmol)溶解于6mL四氢呋喃和水(V:V＝2:1)的混合溶液中，加入氢氧化锂(186mg，4.44mmol)，升温至40℃，搅拌反应1小时。加入20mL乙酸乙酯，有机相依次用饱和碳酸氢钠溶液(10mL×3)和水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(S)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺28f(139mg，浅棕色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):626.2[M+1]
第七步
(S)-N-(2,3-二羟基丙基)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品(S)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-N-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺28f(139mg，0.22mmol)溶解于10mL四氢呋喃中，加入5mL 1M盐酸，搅拌反应4小时。反应液减压浓缩，用制备分离法纯化所得残余物，得到标题产物(S)-N-(2,3-二羟基丙基)-4-(3-氟-2-甲基苯氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺28(70mg，浅棕色固体)，产率：53.8％。
MS m/z(ESI):586.2[M+1]
1H NMR(400MHz,DMSO-d6):δ9.33(s,1H),8.09(t,1H),7.61(dd,1H),7.33-7.42(m,2H),7.17(t,1H),7.06(d,1H),6.69(t,1H),5.04(s,1H),3.39-3.46(m,1H),3.11-3.24(m,3H),3.19(s,3H),2.93-3.00(m,1H),2.06(s,3H).
实施例29
2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000059
第一步
5-(2-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2-甲基-3-羟基-吡啶(55mg，0.50mmol)溶解于5mL四氢呋喃中，加入氢化钠(24mg，0.60mmol)，搅拌反应1小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(2-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮29a(128mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(2-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮29a(128mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝5:1)的混合溶液中，加入氢氧化锂(42mg，1mmol)，搅拌反应4小时。加入50mL乙酸乙酯和10mL水，水相用乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺29b(123g，红棕色油状物)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):615.1[M+1]
第三步
4-(2-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺29b(123mg，0.20mmol)溶解于4mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应1小时。加入50mL乙酸乙酯和15mL水，有机相用1M的盐酸洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺29(9mg，淡棕色固体)，产率：9.1％。
MS m/z(ESI):495.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.89(s,1H),8.43(dd,1H),7.59-7.70(m,4H),7.43(dd,1H),7.38(dd,1H),6.68(t,1H),5.00(s,1H),3.15(s,3H),2.35(s,3H).
实施例30
2-(2-氟-4-碘苯氨基)-1-甲基-4-(5-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000060
第一步
5-(5-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将5-甲基-3-羟基-吡啶(43mg，0.40mmol)溶解于5mL四氢呋喃中，加入氢化钠(16mg，0.40mmol)，搅拌反应1小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(5-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮30a(128mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(5-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(5-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮30a(128mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(42mg，1mmol)，搅拌反应3小时。加入50mL乙酸乙酯和10mL水，水相用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(5-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺30b(122mg，棕色油状物)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):615.0[M+1]
第三步
4-(5-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(5-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺30b(122mg，0.20mmol)溶解于4mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至100℃，搅拌反应4小时。加入50mL乙酸乙酯和15mL水，有机相用水洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物2-(2-氟-4-碘苯氨基)-1-甲基-4-(5-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺30(18mg，类白色固体)，产率：18.2％。
MS m/z(ESI):495.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.79(s,1H),8.36-8.38(m,2H),7.60-7.66(m,4H),7.42-7.44(m,1H),6.63-6.68(m,1H),5.15(s,1H),3.16(s,3H),2.36(s,3H).
实施例31
2-(2-氟-4-碘苯氨基)-1-甲基-4-(6-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000061
Figure PCTCN2014085976-appb-000062
第一步
5-(6-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将6-甲基-3-羟基-吡啶(26mg，0.24mmol)溶解于5mL四氢呋喃中，加入氢化钠(12mg，0.30mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物5-(6-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮31a(128mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):641.1[M+1]
第二步
4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(6-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮31a(128mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(168mg，4mmol)，升温至40℃，搅拌反应1小时。加入50mL乙酸乙酯，有机相用1M氢氧化钠溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺31b(123mg，棕色油状物)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):615.0[M+1]
第三步
4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺31b(123mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应4小时。加入50mL乙酸乙酯和15mL水，有机相用水洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓 缩，用制备分离法纯化所得残余物，得到标题产物2-(2-氟-4-碘苯氨基)-1-甲基-4-(6-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺31(30mg，浅棕色固体)，产率：30.3％。
MS m/z(ESI):495.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),8.38-8.44(m,1H),7.57-7.75(m,4H),7.35-7.49(m,2H),6.65(t,1H),5.09(s,1H),3.15(s,3H),2.51(s,3H).
实施例32
2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基吡啶-4-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000063
第一步
5-(2-甲基吡啶-4-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将2-甲基-4-羟基-吡啶(21mg，0.19mmol)溶解于10mL四氢呋喃中，加入氢化钠(7mg，0.29mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(130mg，0.19mmol)，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(2-甲基吡啶-4-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮32a(122mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(2-甲基吡啶-4-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(2-甲基吡啶-4-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮32a(122mg，0.19mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(80mg，1.91mmol)，搅拌反应2小时。加入50mL乙酸乙酯和10mL水，水相用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-甲基吡啶-4-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺32b(140g，黄色油状物)，产物不经纯化直接进行下一步反应。
第三步
4-(2-甲基吡啶-4-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(2-甲基吡啶-4-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺32b(140mg，0.19mmol)溶解于5mL苯甲醚中，加入氯化铝(127mg，0.96mmol)，升温至100℃，搅拌反应3小时。加入50mL乙酸乙酯和15mL水，有机相用水洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物2-(2-氟-4-碘苯氨基)-1-甲基-4-(2-甲基吡啶-4-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺32(5mg，黄色固体)，产率：5.3％。
MS m/z(ESI):495.1[M+1]
实施例33
2-(2-氟-4-碘苯氨基)-1-甲基-4-(4-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺
Figure PCTCN2014085976-appb-000064
第一步
5-(4-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将4-甲基-3-羟基-吡啶(44mg，0.40mmol)和1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(140mg，0.20mmol)溶解于5mL四氢呋喃中，加入氢化钠(24mg，0.60mmol)，搅拌反应1小时，加入，搅拌反应12小时。反应液减压浓缩，得到粗品标题产物5-(4-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮33a(128mg，黄色液体)，产物不经纯化直接进行下一步反应。
第二步
4-(4-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(4-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮33a(128mg，0.20mmol)溶解于12mL四氢呋喃和水(V:V＝6:1)的混合溶液中，加入氢氧化锂(84mg，2mmol)，搅拌反应2小时。加入50mL乙酸乙酯和10mL水，水相用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(4-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺33b(122g，黄色油状物)，产物不经纯化直接进行下一步反应。
第三步
4-(4-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(4-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺33b(122mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至100℃，搅拌反应12小时。加入50mL二氯甲烷和15mL水，有机相用水洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物2-(2-氟-4-碘苯氨基)-1-甲基-4-(4-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺33(31mg，淡黄色固体)，产率：31.3％。
MS m/z(ESI):495.1[M+1]
1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),8.59(s,1H),8.51-8.53(d,1H),7.60-7.70(m,4H),7.43-7.46(dd,1H),6.68-6.73(t,1H),5.14(s,1H),3.17(s,3H),2.27(s,3H).
测试例：
生物学评价
测试例1、本发明化合物对MEK1激酶活性的测定
体外MEK1激酶活性通过以下的方法进行测试。
本实验使用的MEK激酶：MEK 1(Recombinant Human Protein，Invitrogen，货号PV3093)。
使用试剂盒：Z'-LYTETM Kinase Assay Kit-Ser/Thr 03Peptide(Invitrogen，货号PV3176)。
以下所述的体外细胞实验可测定受试化合物对MEK激酶的增殖抑制活性，测试化合物根据实验所需浓度溶解于二甲基亚砜。配制1×Buffer A(Invitrogen，货号PV3189)；用1×Buffer A稀释ATP得到400μM ATP溶液，将适量Z'-LYTETM Ser/Thr 03Peptide(Invitrogen，货号PV3200)，MEK激酶(MEK 1)酶与1×Buffer A混合；适量Z'-LYTETM Ser/Thr 03phosphoPeptide底物(Invitrogen，货号PV3215)和1×Buffer A配成混合液待用，测试化合物DMSO溶液用1×缓冲液配制成4％DMSO的化合物溶液，在反应孔中加上2.5μL测试化合物DMSO溶液用1×Buffer A，2.5μL 400μM ATP溶液和5μL酶和底物混合液成为10μL反应体系，37℃孵育4小时后，按照Reagent A:Buffer B＝1:1024配制混合液，在反应孔中加入5μL Reagent A(Invitrogen，货号PV3295)和Buffer B(Invitrogen，货号P3127)的混合液，25℃孵育60min后，使用NovoStar酶标仪读荧光，激发波长：400nm，发射波长：445nm和520nm。
本发明化合物的活性：本发明化合物的MEK激酶(MEK 1)生化抑制活性通过以上的试验进行测定，测得的IC50值见表1。
表1本发明化合物对MEK激酶(MEK 1)的抑制活性
实施例编号 IC50/(nM)
1 4.7
2 19.0
3 4.1
4 4.0
5 4.0
6 3.4
7 5.5
8 3.2
9 6.0
10 6.3
11 5.5
12 5.1
13 5.5
14 6.2
15 8.2
16 9.5
17 8.4
18 7.9
19 5.8
20 2.9
21 6.3
22 4.3
23 4.2
24 4.0
25 5.9
26 3.9
27 28.3
28 26.0
29 3.6
30 6.0
31 3.9
32 5.5
33 7.3
结论：本发明化合物对MEK 1激酶活性具有明显的抑制作用。
测试例2、本发明化合物对MEK2激酶的增殖抑制测定
体外MEK2激酶活性通过以下的方法进行测试。
本实验使用的MEK激酶：
MAP2K2(MEK2)Recombinant Human Protein(Invitrogen，Catalog No.PV3615)
MAPK1(ERK2)Recombinant Human Protein(Invitrogen，Catalog No.PV3314)
本实验使用的试剂盒：Z'-LYTETM Kinase Assay Kit-Ser/Thr 03Peptide(Invitrogen，货号PV3176)。
以下所述的体外细胞实验可测定受试化合物对MEK激酶的增殖抑制活性，测试化合物根据实验所需浓度溶解于二甲基亚砜。配制1×Buffer A(Invitrogen，货号PV3189)；用1×Buffer A稀释ATP得到400μM ATP溶液，将适量Z'-LYTETM Ser/Thr 03Peptide(Invitrogen，货号PV3200)，MEK激酶(MEK 2)酶、(ERK2)酶与1×Buffer A混合；适量Z'-LYTETM Ser/Thr 03phosphoPeptide底物(Invitrogen，货号PV3215)和1×Buffer A配成混合液待用，测试化合物DMSO溶液用1×缓冲液配制成4％DMSO的化合物溶液，在反应孔中加上2.5μL 4％DMSO的化合物缓冲液溶液，2.5μL 400μM ATP溶液和5μL酶和底物混合液成为10μL反应体系，25℃孵育1.5小时后，按照Reagent A:Buffer B＝1:1024配制混合液，在反应孔中加入5μL Reagent A(Invitrogen，货号PV3295)和Buffer B(Invitrogen，货号P3127)的混合液，25℃孵育60min后，使用NovoStar酶标仪读荧光，激发波长：400nm，发射波长：445nm和520nm。
本发明化合物的MEK激酶(MEK 2)生化抑制活性通过以上的试验进行测定，测得的IC50值见表3。
表3本发明化合物对MEK激酶(MEK 2)的抑制活性
实施例 IC50/(nM)
1 108.3
3 19.8
22 120.8
29 216.8
31 350.9
结论：本发明化合物对MEK 2激酶活性具有明显的抑制作用。
测试例3、本发明化合物对Colo205的增殖抑制测定
本实验使用的细胞株来源：Colo205(中科院细胞库，货号TCHu102)。
以下所述的体外细胞试验可测定受试化合物对人结肠癌细胞细胞株的增殖抑制活性，其活性可用IC50值来表示。此类试验的一般方案如下：首先将待测细胞株(购于中科院细胞库)以适宜细胞浓度4000个细胞/mL介质接种在96孔培养板上，然后将细胞在二氧化碳恒温箱内37℃进行培养，让它们生长至过夜，更换培养基为加有一系列浓度递度(10000nM、1000nM、100nM、10nM、1nM、0.1nM)受试化合物溶液的培养基，将培养板重新放回培养箱，连续培养72个小时。72小时后，可用CCK8(细胞计算试剂盒8(Cell Counting Kit-8)，货号：CK04，购于同仁化学)方法进行测试化合物对于抑制细胞增殖活性。IC50值可通过一系列不同浓度下，受试化合物对于细胞的抑制数值进行计算。
本发明化合物生物活性由上述分析所得，计算所得的IC50值如下表2：
表2本发明化合物对Colo205细胞的增殖抑制活性
实施例编号 IC50/(nM)
1 0.7
2 4.7
3 0.04
4 0.8
7 0.4
8 0.5
9 0.3
10 4.3
11 4.3
12 0.7
13 2.9
14 4.2
15 10.2
16 11.5
17 2.0
18 1.4
19 0.8
20 1.7
21 10.2
22 6.1
23 0.4
24 3.1
25 1.0
29 0.8
31 3.6
32 4
结论：本发明优选化合物均对Colo205细胞具有明显的增殖抑制活性。
测试例4、本发明化合物对人结肠癌细胞HCT116的增殖抑制测定
以下所述的体外细胞试验可测定受试化合物对人结肠癌细胞的增殖抑制活性，其活性可用IC50值来表示。
本实验使用的细胞株：HCT116(中科院细胞库，货号TCHu 99)
此类试验的一般方案如下：首先将待测细胞株以适宜细胞浓度1000个细胞/孔接种于384孔细胞培养板上，然后将细胞放在37℃、5％二氧化碳恒温箱内培养，让它们生长至过夜，更换培养基为加有一系列浓度梯度(1000nM、250nM、62.50nM、15.63nM、3.91nM、0.98nM、0.24nM、0.06nM、0.015nM、0.004nM)受试化合物溶液的培养基，将培养板重新放回培养箱，连续培养72个小时。72小时后，可用CCK8(细胞计算试剂盒8(Cell Counting Kit-8)，货号：CK04，购于同仁化学)方法进行测试化合物抑制细胞增殖活性。IC50值可通过一系列不同浓度下，受试化合物对于细胞的抑制数值进行计算。
本发明化合物生物活性由上述分析所得，计算所得的IC50值如下表4：
表4本发明化合物对HCT116细胞的增殖抑制活性
实施例 IC50/(nM)
1 8.6
3 0.06
22 10.3
29 8.9
31 36.4
结论：本发明优选化合物均对HCT116细胞具有明显的增殖抑制活性。
本发明化合物对体外CYP酶抑制评价
测试例5、本发明实施例1、实施例3、实施例4、实施例22、实施例29、实施例30和实施例31化合物的体外CYP酶抑制测试
1、摘要
采用人肝微粒体孵化体系，通过代谢物的生产量来反映各种酶的活性。考察化合物对CYP1A2、CYP2C9、CYP2C6、CYP3A4m、CYP3A4t和CYP2C19酶的抑制情况，测定IC50值(酶活性被抑制50％时待测化合物的浓度)。
2、试验方案
2.1试验药品
实施例1、实施例3、实施例4、实施例22、实施例29、实施例30和实施例31化合物
2.2.材料
2.2.1.磷酸缓冲液(PBS)的制备
称取18.303g K2HPO4，2.695g KH2PO4，11.175g KCl，372.2mg EDTA，用超纯水稀释至1000mL，即得pH 7.4的磷酸缓冲盐溶液(EDTA为1mM，KCl为0.15M)，放置4℃冰箱保存。
2.2.2.NADPH的称量及制备
40mM NADPH溶液的配制：称取100mg NADPH(MW＝833.4g/mol)标准品，用3ml PBS缓冲液溶解，混匀。
2.2.3.肝微粒体PBS溶液的配置
0.25mg/ml肝微粒体溶液的配制：采用PBS缓冲液将人肝微粒(20mg/ml)稀释至0.25mg/mL。
2.2.4.待测化合物反应液的制备
称取适量的待测物标准品，用DMSO稀释至50mM，得到储备液I；采用PBS将其稀释至100μM，即为孵化反应用的药液。
2.2.5.CYP探针底物和选择性抑制剂的配制
Figure PCTCN2014085976-appb-000065
上述探针底物和阳性对照抑制剂终浓度均采用PBS配制。
3、实验过程
制备反应混合物：60μL
试剂 体积(uL)
人肝微粒体(0.25mg/ml) 40μL
探针底物 10μL
待测化合物/阳性对照抑制剂 10μL
上述混合物在37℃.条件下预孵育5分钟。向反应混合物加入40μL NADPH溶液(2.5mM，PBS配制)，在37℃条件下孵化20分钟。所有孵育样品设双样本。加入300μL冰冷乙腈终止反应，加入100μl内标，混匀。在3500rpm离心10分钟。上清液转移至LC-MS/MS分析。
4、数据分析
通过代谢物的生产量来反映各种酶的活性。采用单点法计算，公式如下：
Figure PCTCN2014085976-appb-000066
[假设Hill斜率(Hill slope)＝1]
C0＝待测化合物的浓度
根据文献报道：IC50>10μM属于较弱的抑制，1μM<IC50<10μM属于中等程度抑制，IC50<1μM属于强烈抑制。
5、体外CYP酶抑制测试结果
本发明化合物的体外CYP酶抑制测试结果如下所示。
Figure PCTCN2014085976-appb-000067
本发明的优选化合物对于CYP1A2、CYP2C9、CYP2C6、CYP3A4m、CYP3A4t和CYP2C19酶具有较弱程度的抑制作用，因此在临床给药时，药物代谢性相互作用可能性较低。
药代动力学评价
测试例6、本发明实施例1、实施例22、实施例29和实施例31化合物的药代动力学测试
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例1、实施例22、实施例29和实施例31化合物后不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例1、实施例22、实施例29和实施例31化合物
2.2试验动物
健康成年SD大鼠16只，分成4组，每组4只，雌雄各半，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。
2.3药物配制
称取适量样品，加入40μL吐温80，加入0.5％CMC-Na，超声制成1mg/ml混悬液。
2.4给药
SD大鼠16只，分成4组，每组4只，雌雄各半，禁食一夜后分别灌胃给药，剂量为10mg/kg，给药体积10ml/kg。
3、操作
于给药前及给药后0.5，1，2，4，6，8，11，24，48小时由眼眶采血0.1ml，置于肝素化试管中，3500rpm离心10分钟，分离血浆，于-20℃保存。给药后2小时进食。
用LC/MS/MS法测定灌胃给药后大鼠血浆中的待测化合物含量。分析方法的线性范围为1.00-2000ng/ml，定量下限为1.00ng/ml；血浆样品经沉淀蛋白预处理后进行分析。
4、药代动力学参数结果
本发明化合物的药代动力学参数如下表6：
Figure PCTCN2014085976-appb-000068
结论：本发明化合物的药代吸收良好，具有明显的药代吸收效果。

Claims (21)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐：
    Figure PCTCN2014085976-appb-100001
    其中：
    R1选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代；
    R2或R3各自独立地选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、氰基、硝基、烯基、炔基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代；
    R4选自芳基或杂芳基，其中所述的芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、氰基、羟基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代；
    R5选自氢原子、烷基、烯基或炔基，其中所述的烷基、烯基或炔基各自独立地任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基或卤代烷基的取代基所取代；
    R6选自氢原子、卤素或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、氰基、硝基、烷氧基、环烷基、杂环基、芳基或杂芳基的取代基所取代；
    R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    R8或R9各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    或者，R8或R9与相连接的氮原子一起形成杂环基，其中所述的杂环基含有一个或多个N、O或S(O)m杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    m为0、1或2；并且
    n为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R1选自芳基或杂芳基，其中所述的芳基或杂芳基任选进一步被一个或多个卤素、氰基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代，并且R7、R8、R9、m和n如权利要求1中所定义。
  3. 根据权利要求1或2任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R1选自苯基或吡啶基，其中所述的苯基或吡啶基任选进一步被一个或多个选自烷基、卤素、卤代烷基、-OR7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7、或-NHS(O)mR7的取代基所取代，并且R7和m如权利要求1中所定义。
  4. 根据权利要求1～3任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R2选自氢原子，R3选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、氰基、硝基、烯基、炔基、杂环基、芳基、杂芳基、-OR7、-C(O)OR7、-OC(O)R7、-O(CH2)nC(O)OR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NHS(O)mR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9的取代基所取代，并且R7、R8、R9、m和n如权利要求1中所定义。
  5. 根据权利要求1～4任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R4为芳基，其中所述的芳基任选进一步被一个或多个卤素所取代。
  6. 根据权利要求1～5任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R5为烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基或卤代烷基的取代基所取代。
  7. 根据权利要求1～6任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R6选自氢原子或卤素。
  8. 根据权利要求1～7任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐：
    Figure PCTCN2014085976-appb-100002
    Ra或Rb选自氢原子、卤素、烷基或卤代烷基；
    R1选自苯基或吡啶基，其中所述的苯基或吡啶基任选进一步被一个或多个选自烷基、卤素、卤代烷基、-OR7、-C(O)NHR7、-NHC(O)R7、-NHC(O)OR7或-NHS(O)mR7的取代基所取代；
    R6选自氢原子、卤素或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、氰基、硝基、烷氧基、环烷基、杂环基、芳基或杂芳基的取代基所取代；并且
    R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代。
  9. 根据权利要求1～8任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中R7选自氢原子、烷基、环烷基或杂环基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基的取代基所取代。
  10. 根据权利要求1～9任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，其中所述化合物选自：
    Figure PCTCN2014085976-appb-100003
    Figure PCTCN2014085976-appb-100004
    Figure PCTCN2014085976-appb-100005
    或
    Figure PCTCN2014085976-appb-100006
  11. 一种通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐：
    Figure PCTCN2014085976-appb-100007
    其中：
    R1、R4、R5或R6的定义如权利要求1中所述；
    PG选自烷基或氨基保护基，其中所述的氨基保护基优选为苄基，所述的烷基或苄基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、环烷基、杂环基、杂芳基或-OR7的取代基所取代；并且
    R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代。
  12. 根据权利要求11所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，其中所述的化合物选自：
    Figure PCTCN2014085976-appb-100008
    Figure PCTCN2014085976-appb-100009
    或
    Figure PCTCN2014085976-appb-100010
  13. 一种制备根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐的方法，该方法包括：
    Figure PCTCN2014085976-appb-100011
    通式(IA)化合物在碱性条件下进行开环反应，任选进一步脱去氨基保护基PG，得到通式(I)化合物；
    其中：R1～R6的定义如权利要求1中所述；
    PG选自烷基或氨基保护基，其中所述的氨基保护基优选为苄基，所述的烷基或苄基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基或-OR7的取代基所取代；并且
    R7选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代。
  14. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1～10任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  15. 根据权利要求1～10任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或根据权利要求14所述的药物组合物在制备抑制MEK的药物中的用途。
  16. 根据权利要求1～10任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或根据权利要求14所述的药物组合物在制备治疗炎性病症、自身免疫性疾病、心血管病症、增殖性疾病或感受伤害的病症的药物中的用途。
  17. 根据权利要求1～10任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或根据权利要求14所述的药物组合物在制备治疗癌症的药物中的用途， 其中所述的癌症选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤，优选为结肠直肠癌或肺癌。
  18. 根据权利要求17所述的用途，其中所述的药物进一步包含另外一种或多种抗癌剂。
  19. 一种抑制MEK活性的方法，其包括给予所需患者治疗有效量的根据权利要求1～10任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或根据权利要求14所述的药物组合物。
  20. 一种治疗炎性病症、自身免疫性疾病、心血管病症、增殖性疾病或感受伤害的病症的方法，其包括给予所需患者治疗有效量的根据权利要求1～10任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或根据权利要求14所述的药物组合物，其中所述的增殖性疾病可以为癌症。
  21. 一种治疗癌症的方法，其包括给予所需患者治疗有效量的根据权利要求1～10任意一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐，或根据权利要求14所述的药物组合物，其中所述癌症选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤，优选为结肠直肠癌或肺癌。
PCT/CN2014/085976 2013-10-25 2014-09-05 吡啶酮类衍生物、其制备方法及其在医药上的应用 WO2015058589A1 (zh)

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JP2018509407A (ja) * 2015-03-27 2018-04-05 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． ＭＥＫキナーゼ阻害剤のｐ−トルエンスルホン酸塩、およびその結晶形およびその製造法
CN104892499A (zh) * 2015-06-26 2015-09-09 江西省科学院应用化学研究所 一种2-吡啶酮类衍生物的合成方法
WO2018095403A1 (zh) 2016-11-25 2018-05-31 江苏恒瑞医药股份有限公司 一种吡啶酮类衍生物药物组合物及其制备方法
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CN108314645A (zh) * 2017-01-18 2018-07-24 上海映诺济生物科技有限公司 一类具有抗细胞增殖活性的化合物、制备方法和用途
WO2018233696A1 (zh) 2017-06-23 2018-12-27 基石药业 作为mek抑制剂的类香豆素环类化合物及其应用
TWI801394B (zh) * 2017-06-23 2023-05-11 大陸商基石藥業（蘇州）有限公司 作為mek抑制劑的類香豆素環類化合物及其應用
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WO2020125747A1 (zh) * 2018-12-21 2020-06-25 基石药业（苏州）有限公司 一种mek抑制剂的晶型、无定形及其应用
CN112912380B (zh) * 2018-12-21 2023-08-11 基石药业（苏州）有限公司 一种mek抑制剂的晶型、无定形及其应用
WO2020156162A1 (zh) * 2019-01-29 2020-08-06 贝达药业股份有限公司 Mek抑制剂及其在医药上的应用
CN113423398A (zh) * 2019-01-29 2021-09-21 贝达药业股份有限公司 Mek抑制剂及其在医药上的应用
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021018112A1 (zh) * 2019-07-29 2021-02-04 江苏恒瑞医药股份有限公司 一种1，6-二氢吡啶-3-甲酰胺衍生物的制备方法
WO2021047573A1 (zh) * 2019-09-11 2021-03-18 江苏恒瑞医药股份有限公司 一种mek抑制剂与cdk4/6抑制剂联合在制备***的药物中的用途
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
CN114605408A (zh) * 2022-03-30 2022-06-10 沈阳药科大学 5-羟基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制法和应用
US11878958B2 (en) 2022-05-25 2024-01-23 Ikena Oncology, Inc. MEK inhibitors and uses thereof

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